Sodium salt of 4-oxo-10-(2,3-dimethylpentanamido)-4H-pyrimido[1,2-c]quinozoline-3-carboxylic acid

ABSTRACT

Quinazoline derivatives of the formulae: ##STR1## wherein A 1  is ##STR2## A 2  is ##STR3## R 1  is hydrogen, carboxy or esterified carboxy, R a   1  and R b   1  are esterified carboxy, 
     R 2  and R 3  are hydrogen, alkyl, halogen, nitro, amino, alkoxy, aryloxy, alkylthio, alkylpiperazinyl, acylamino or dialkylamino which may be substituted with hydroxy, 
     R 4  is hydrogen, alkyl, hydroxy, alkoxy, alkenyloxy, dialkylamino or 2,2-dialkoxycarbonylvinylamino 
     R a   4  is hydrogen, alkyl, hydroxy, alkoxy, alkenyloxy or dialkylamino, 
     R 5  is alkyl or alkenyl, and 
     R 6  is carboxy or esterified carboxy.

This application is a continuation-in-part of parent application Ser.No. 210,340 filed on Nov. 25, 1980, now U.S. Pat. No. 4,377,580.

This invention relates to new quinazoline derivatives. Moreparticularly, it relates to new quinazoline derivatives, to processesfor preparation thereof, to a pharmaceutical composition comprising thesame, and to a method of use of the same in the treatment of symptomsassociated with allergic manifestations, e.g. asthmatic conditions.

Accordingly, it is an object of this invention to provide newquinazoline derivatives which are useful as antiallergic agent.

Another object of this invention is to provide processes for preparingthe quinazoline derivatives.

Further object of the invention is to provide a pharmaceuticalcomposition comprising the quinazoline derivatives.

Quinazoline derivatives of this invention include quinazoline compoundsof the formula: ##STR4## wherein R_(a) ¹ and R_(b) ¹ are esterifiedcarboxy,

R² and R³ are hydrogen, alkyl, halogen, nitro, amino, alkoxy, aryloxy,alkylthio, alkylpiperazinyl, acylamino or dialkylamino which may besubstituted with hydroxy,

A¹ is a group of the formula: ##STR5## in which R⁴ is hydrogen, alkyl,hydroxy, alkoxy, alkenyloxy, dialkylamino or2,2-dialkoxycarbonylvinylamino, and

R⁵ is alkyl or alkenyl, and

pyrimidoquinazoline compounds of the formula: ##STR6## wherein R¹ is ahydrogen, carboxy or esterified carboxy,

A² is a group of the formula: ##STR7## in which R_(a) ⁴ is hydrogen,alkyl, hydroxy, alkoxy, alkenyloxy or dialkylamino,

R⁶ is carboxy or esterified carboxy and

R⁵ is the same as defined above, and

R² and R³ are each as defined above.

Particulars of the above definitions and suitable examples thereof areexplained as follows.

As to the term "lower" used in the specification and claims, it is to beunderstood that it means the one having 1 to 6 carbon atom(s), unlessotherwise provided.

Suitable esterified carboxy for R¹, R_(a) ¹, R_(b) ¹ and R⁶ may be loweralkoxycarbonyl having 2 to 7 carbon atom(s) (e.g. methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,isobutoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl,hexyloxycarbonyl) and the like. Further, the esterified carboxy of R_(a)¹ and R_(b) ¹ may be linked together to form a group of the formula:##STR8##

Suitable alkyl for R², R³, R⁴, R_(a) ⁴ and R⁵ may be straight orbranched lower alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl,isobutyl, t-butyl, pentyl, hexyl).

The halogen for R² and R³ may be fluorine, chlorine, bromine and iodine.

Suitable alkoxy for R², R³, R⁴ and R_(a) ⁴ may be straight or branchedlower alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy,isobutoxy, t-butoxy, pentyloxy, hexyloxy).

Suitable aryloxy for R² and R³ may be phenoxy, naphthyloxy, tolyloxy orthe like.

Suitable alkylthio for R² and R³ may be straight or branched loweralkylthio (e.g. methylthio, ethylthio, propylthio, isopropylthio,butylthio, isobutylthio, t-butylthio, pentylthio, hexylthio).

Suitable dialkylamino for R², R³, R⁴ and R_(a) ⁴ may bedi(lower)alkylamino (e.g. dimethylamino, diethylamino, dipropylamino,diisopropylamino, dibutylamino), and the alkyl moiety of saiddialkylamino group may be substituted with hydroxy to formbis(hydroxyalkyl)amino (e.g. bis(hydroxyethyl)amino, etc.).

Suitable alkylpiperazinyl for R² and R³ may be 4-lower alkyl piperazinyl(e.g. 4-methylpiperazinyl, 4-ethylpiperazinyl, 4-propylpiperazinyl,4-isopropylpiperazinyl, 4-t-butylpiperazinyl, 4-pentylpiperazinyl,4-hexylpiperazinyl).

The acylamino group for R² and R³ includes both of monoacylamino groupand diacylamino group. Acyl moiety of the acylamino group may includethe residue of organic carboxylic acid and organic sulfonic acid.Suitable acyl may be alkanoyl including lower alkanoyl (e.g. formyl,acetyl, propionyl, butyryl, isobutyryl, 3,3-dimethylbutyryl, valeryl,isovaleryl, pivaloyl) and higher alkanoyl having 7 to 18 carbon atoms(e.g. heptanoyl, 2,3-dimethylpentanoyl, lauroyl, myristoyl, palmitoyl,stearoyl), lower alkoxalyl having 3 to 9 carbon atoms (e.g. methoxalyl,ethoxalyl, propoxalyl), lower cycloalkanecarbonyl having 4 to 8 carbonatoms (e.g. cyclopentanecarbonyl, cyclohexanecarbonyl,cycloheptanecarbonyl), lower (C₃ -C₇) cycloalkyl(lower)alkanoyl (e.g.3-cyclopentylpropionyl), aroyl (e.g. benzoyl, naphthoyl, toluoyl,xyloyl, phthaloyl), ar(lower)alkanoyl (e.g. phenylacetyl), loweralkanesulfonyl (e.g. mesyl, ethanesulfonyl, propanesulfonyl).

Suitable alkenyloxy for R⁴ and R_(a) ⁴ may be lower alkenyloxy having 2to 6 carbon atoms (e.g. vinyloxy, allyloxy, 1-propenyloxy,3-butenyloxy).

Suitable 2,2-dialkoxycarbonylvinylamino for R⁴ may be2,2-di(lower)alkoxycarbonylvinylamino (e.g.2,2-dimethoxycarbonylvinylamino, 2,2-diethoxycarbonylvinylamino).

Suitable alkenyl for R⁵ may be lower alkenyl having 2 to 6 carton atoms(e.g. vinyl, allyl, 2-propenyl, 3-butenyl, 3-pentenyl, 5-hexenyl, etc.).

Quinazoline derivatives of this invention can be prepared by variousprocesses as illustrated below. ##STR9## wherein R_(a) ¹, R_(b) ¹, R²,R³, A¹ and A² are each as defined above,

R_(a) ² is acyl, and

R⁷ is alkoxy.

The processes as illustrated above are explained in the following inmore detail.

Process 1

The object compound (I) can be prepared by reacting a compound (III) orits salt with a compound (IV).

Preferred examples of the alkoxy for R⁷ of the compound (IV) may belower ones (e.g. methoxy, ethoxy, propoxy, etc.).

The salt of the compound (III) may be a salt with an inorganic ororganic acid such as hydrochloric acid, hydrobromic acid,p-toluenesulfonic acid, etc.

The starting compounds (III) include known and novel ones. The knowncompounds, e.g. 4-aminoquinazoline, 2-chloro-4-aminoquinazoline,2-hydroxy-4-aminoquinazoline and 2-methoxy-4-aminoquinazoline can beprepared by the method described in Journal of the Chemical Society (C)1284 (1969), Chemical Abstracts 54, 24778b and 9939C (1960), and the newcompounds (III) can be prepared in the similar manner thereto. Themethod for preparing said new compound is to be referred to Preparationof starting compounds as described hereinafter.

The reaction of this process is usually conducted in a solvent such asN,N-dimethylformamide, ethanol, propanol, isobutyl alcohol,tetrahydrofuran, diphenylether, chloroform, toluene, xylene, or thelike, at a temperature range from cooling to heating.

This reaction may be carried out in the presence of a base such asalkali metal hydride (e.g. sodium hydride), alkali metal amide (e.g.sodium amide) alkali metal alkoxide (e.g. potassium t-butoxide),diazabicyclo compound (e.g. 1,5-diazabicyclo[3,4,0]nonene-5,1,5-diazabicyclo[5,4,0]undecene-5, etc.), or the like.

When this reaction is conducted at relatively high temperature, theremay be occasionally produced a ring closure compound, i.e.primidoquinazoline compound (II). Thus produced pyrimidoquinazolinecompound can be transformed to quinazoline compound (I) by treating itwith a strong base such as alkali metal alkoxide (e.g. sodium ethoxide).This case is also included within the scope of this process.

Process 2

The object compound (Ib) can be prepared by reducing a compound (Ia).

The reaction can preferably be conducted by catalytic reduction.

The catalytic reduction is usually conducted at ambient temperature orunder cooling in an inert solvent (e.g. N,N-dimethylformamide, ethanol,propanol, isobutyl alcohol, tetrahydrofuran, chloroform, ethyl acetate,acetic acid, etc.) by using a conventional catalyst such as Raneynickel, palladium on carbon, or the like.

Process 3

The object compound (Ic) can be prepared by reacting a compound (Ib)with an acylating agent.

The acylating agent to be used in this reaction includes an organic acid(i.e. R_(a) ² OH, in which R_(a) ² is as defined above) and its reactivederivative.

Suitable examples of the organic acids are to be referred to thedescriptions of the suitable acyl moiety of the acylamino group for R²of the compound (II).

The suitable reactive derivative may be a conventional ones such as anacid halide (e.g. acid chloride, acid bromide, etc.), an acid azide, anacid anhydride, an activated amide, an activated ester, etc.

When free acid is used as an acylating agent, the acylation reaction maypreferably be conducted in the presence of a conventional condensingagent.

The reaction is usually conducted in a solvent such asN,N-dimethylformamide, dimethylsulfoxide, tetrahydrofuran,dichloromethane, chloroform, pyridine or a mixture thereof.

The reaction can also be conducted preferably in the presence of anorganic or inorganic base such as alkali metal (e.g. sodium), alkalineearth metal (e.g. calcium), alkali or alkaline earth metal hydride (e.g.sodium hydride, calcium hydride, etc.), alkali or alkaline earth metalhydroxide (e.g. sodium hydroxide, potassium hydroxide, calciumhydroxide, etc.), alkali or alkaline earth metal carbonate orbicarbonate (e.g. sodium carbonate, potassium carbonate, sodiumbicarbonate), alkali or alkaline earth metal alkoxide (e.g. sodiumethoxide, lithium methoxide, magnesium methoxide), trialkylamine (e.g.triethylamine), pyridine, bicyclodiaza compound (e.g.1,5-diazabicyclo[3,4,0]nonene-5, 1,5-diazabicyclo[5,4,0]undecene-5,etc.) and the like.

The reaction may preferably be conducted within the range of cooling toambient temperature.

When this acylation reaction is conducted with an excess amount of theacylating agent, there may occasionally be produced N,N-diacylatedcompound, and this case is also included within the scope of thisprocess.

Process 4

The object compound (IIa) can be prepared by heating a compound (Id).

This reaction is usually conducted under heating, preferably at160°-270° C. in the presence or absence of a solvent such asN,N-dimethylformamide, diphenylether, biphenyl, paraffin or the like.The optimum reaction conditions can be selected from the above reactionconditions according to kinds of the starting compound.

Process 5

The object compound (IIb) can be prepared by subjecting a compound (IIa)to selective hydrolysis of the ester.

This reaction is usually conducted by heating a compound (IIa) in thepresence of lithium iodide in an inert solvent such asN,N-dimethylformamide, collidine, lutidine, pyridine and the like, andthen treating the resultant compound with water.

The object compound prepared by each process as mentioned above can beisolated and purified in a conventional manner.

The object compound, quinazoline derivatives (I) and (II) possess strongantiallergic activity and anti-inflammatory activity. Accordingly, theobject compound of this invention is useful for the treatment ofsymptoms associated with allergic diseases such as allergic asthma,allergic rhinitis, urticaria, pollenosis, allergic conjunctivitis,atopic dermatitis, ulcerative colitis, alimentary allergy (e.g. milkallergy), bird fancier's disease, aphthous stomatitis and the like. Forillustrating purpose, the antiallergic activity of some representativecompounds of the object compounds (I) and (II) are shown in thefollowing.

TEST I [Inhibitory effect on PCA (Passive Cutaneous Anaphylaxis)reaction] (1) Test compound

(a) Test compound of the formula: ##STR10##

    ______________________________________                                        Test compound                                                                 No.       R.sup.2         R.sup.3  R.sup.4                                    ______________________________________                                        1         H               H        H                                          2         CH.sub.3        H        H                                          3         C.sub.2 H.sub.5 H        H                                          4         CH.sub.3 (CH.sub.2).sub.2H                                                                    H                                                   5         CH.sub.3 (CH.sub.2).sub.3                                                                     H        H                                          6         H               CH.sub.3 H                                          7         CH.sub.3        CH.sub.3 H                                          8         NO.sub.2        H        H                                          9         H               CH.sub.3 O                                                                             H                                          10                                                                                                      H        H                                          11                                                                                       ##STR11##      H        H                                          12                                                                                       ##STR12##      H        H                                          13        CH.sub.3 CONH   H        H                                          14        C.sub.2 H.sub.5 CONH                                                                          H        H                                          15        η-C.sub.3 H.sub.7 CONH                                                                    H        H                                          16                                                                                       ##STR13##      H        H                                          17        C.sub.2 H.sub.5 OCOCONH                                                                       H        H                                          18                                                                                       ##STR14##      H        H                                          19                                                                                       ##STR15##      H        H                                          20        H               H        CH.sub.3 O                                 ______________________________________                                    

(b) Test Compound No. 21 ##STR16## (c) Test Compound No. 22 ##STR17##(d) Test compound of the formula: ##STR18##

    __________________________________________________________________________    Test Compound                                                                 No.     R.sup.2       R.sup.3 R.sub.a.sup.4                                   __________________________________________________________________________    23      H             H       H                                               24      CH.sub.3      H       H                                               25      C.sub.2 H.sub.5                                                                             H       H                                               26      η-C.sub.3 H.sub.7                                                                       H       H                                               27      η-C.sub.4 H.sub.9                                                                       H       H                                               28      H             CH.sub.3                                                                              H                                               29      Cl            H       H                                               30      H             Cl      H                                               31      NO.sub.2      H       H                                               32      H             CH.sub.3 O                                                                            H                                               33                                                                                                  H       H                                               34                                                                                     ##STR19##    H       H                                               35      CH.sub.3 CONH H       H                                               36      H             CH.sub.3 CONH                                                                         H                                               37      C.sub.2 H.sub.5CONH                                                                         H       H                                               38      η-C.sub.3 H.sub.7 CONH                                                                  H       H                                               39                                                                                     ##STR20##    H       H                                               40      (CH.sub.3).sub.3 CCONH                                                                      H       H                                               41      η-C.sub.5 H.sub.11 CONH                                                                 H       H                                               42      C.sub.2 H.sub.5 OCOCONH                                                                     H       H                                               43                                                                                     ##STR21##    H       H                                               44                                                                                     ##STR22##    H       H                                               45                                                                                     ##STR23##    H       H                                               46      H             H       CH.sub.3                                        47      H             H       HO                                              48      H             H       CH.sub.3 O                                      49      H             H       CH.sub.2CHCH.sub.2 O                            50      C.sub.2 H.sub.5                                                                             H       HO                                              __________________________________________________________________________

(e) Test Compound No. 51 ##STR24## (f) Test Compound No. 52 ##STR25##(g) Test Compound No. 53 ##STR26## (h) Test Compound No. 54 ##STR27##(i) Test Compound No. 55 ##STR28## (j) Test Compound No. 56 ##STR29##(k) Test Compound No. 57 ##STR30##

(2) Test method

(a) Preparation of antiserum

A solution of egg albumin (2 mg) in B. pertussis-diphtheria-tetanusmixed vaccine (1 ml) was mixed with Freund incomplete adjuvant (1 ml) togive an emulsion. The emulsion was given subcutaneously in a single doseof 1 ml divided equally (0.25 ml) to the four foot pads of male SD(Sprague-Dawley) strain rats aged 8 weeks, each weighing about 300 g.

10 days after the immunization, blood samples were collected fromfemoral artery of the rats and allowed to stand under ice-cooling for 5hours. The separated supernatant was centrifuged at 4° C. (10,000r.p.m.×1 hour). The antisera thus obtained were stored at -80° C. priorto use.

(b) Inhibitory effect on P.C.A.

Male SD-strain rats aged 8 weeks, weighing 290 to 330 g, were used forPCA reaction with the homologus reaginic antiserum as prepared above.Each 0.1 ml of 64 fold diluted antiserum were injected intradermally atseparate sites on the back of rats clipped free of hair, and 48 hourslater, 1 ml of aqueous solution containing each 5 mg of the egg albuminand Evans blue was injected intravenously to evoke PCA reaction. Testcompound was given to the animals orally 60 minutes or intravenously 5minutes before the challenge with antigen. Control group receivedvehicle. Each dose group consisted of 5 animals. One hour after thechallenge with antigen, the animals were sacrificed and then skinned.Dye spots caused with antiserum were investigated for their size on thereversed side of the skin, respectively. The results were expressed bypercent inhibition values calculated from averaged values of the longestand shortest diameters for each spot in comparison with those in controlgroup.

(3) Test results

Test results are shown in the following table.

    ______________________________________                                               Inhibitory effect (%)                                                  Test Com-                                                                              Intravenous      Oral administra-                                    pound No.                                                                              administration (10 mg/kg)                                                                      tion (100 mg/kg)                                    ______________________________________                                        1        100              *                                                   2        100              *                                                   3        100              *                                                   4        85.9             *                                                   5        34.8             *                                                   6        100              *                                                   7        42.9             *                                                   8        52.7             *                                                   9        56.3             *                                                   10       24.4             *                                                   11       100              *                                                   12       51.2             *                                                   13       100              *                                                   14       *                77.4                                                15       *                58.1                                                16       100              51.6                                                17       100              *                                                   18       100              *                                                   19       *                73.7                                                20       37.6             *                                                   21       75.4             *                                                   22       100              *                                                   23       100              *                                                   24       100              *                                                   25       100              *                                                   26       100              *                                                   27       100              *                                                   28       100              *                                                   29       100              *                                                   30       100              *                                                   31       64.9             *                                                   32       67.5             *                                                   33       100              *                                                   34       100              *                                                   35       *                72.7                                                36       100              *                                                   37       *                74.2                                                38       100              *                                                   39       *                75.8                                                40       100              *                                                   41       *                100                                                 42       100              *                                                   43       100              *                                                   44       0                49.1                                                45       100              *                                                   46       76.3             *                                                   47       100              *                                                   48       100              57.5                                                49       83.1             *                                                   50       39.8             *                                                   51       100              100                                                 52       100              *                                                   53       85.0             *                                                   54       48.4             *                                                   55       91.0             *                                                   56       100              24.2                                                57       100              100                                                 ______________________________________                                          Note:                                                                        *Not tested.                                                             

TEST II [Inhibitory effect on PCA (Passive Cutaneous Anaphylaxis)reaction] (1) Test compound

(a) Test compound No. 58 ##STR31## (b) Test compound of the formula:##STR32##

    ______________________________________                                        Test compound                                                                 No.          R.sup.1     R.sup.2                                              ______________________________________                                        59           --COOCH.sub.3                                                                             --NHCOC(CH.sub.3).sub.3                              60           --COOH      --NHCOC(CH.sub.3).sub.3                              61           --COOC.sub.2 H.sub.5                                                                      --NHCOCH.sub.2 C(CH.sub.3).sub.3                     62           --COOH      --NHCOCH.sub.2 C(CH.sub.3).sub.3                     63           --COOH      --NHCOCH(CH.sub.3).sub.2                             64           --COOH      --NHCOCH(C.sub.2 H.sub.5).sub.2                      ______________________________________                                    

(2) Test method

This test was carried out in substantially the same manner as describedin TEST I, excepting that 32 fold diluted antiserum was used in place of64 fold diluted antiserum for passive sensitization.

(3) Test results

Test results are shown in the following table.

    ______________________________________                                                Inhibitory effect (%)                                                 Test Com- Intravenous     Oral administra-                                    pound No. administration (1 mg/kg)                                                                      tion (100 mg/kg)                                    ______________________________________                                        58        42.1            *                                                   59        100             *                                                   60        100             63                                                  61        100             *                                                   62        100             *                                                   63        100             *                                                   64        100             *                                                   ______________________________________                                         Note:                                                                         *Not tested.                                                             

The quinazoline derivatives (I) and (II) of this invention can be usedas an active antiallergic agent either in free form or in the form ofthe pharmaceutically acceptable salt such as a salt with inorganic ororganic acid, a salt with inorganic or organic base and a salt with anamino acid.

The object compound (I) and (II) or its pharmaceutically acceptable saltcan usually be administered to mammals including human beings in theform of a conventional pharmaceutical composition such as capsule,microcapsule, tablet, granule, powder, troche, syrup, aerosol,inhalation, solution, injection, suspension, emulsion, suppository,ointment, or the like.

The pharmaceutical composition of this invention can contain variousorganic or inorganic carrier materials, which are conventionally usedfor pharmaceutical purpose, such as excipient (e.g. sucrose, starch,mannit, sorbit, lactose, glucose, cellulose, talc, calcium phosphate,calcium carbonate, etc.), binding agent (cellulose, methyl cellulose,hydroxypropylcellulose, polypropylpyrrolidione, gelatin, gum arabic,polyethyleneglycol, sucrose, starch, etc.), disintegrator (e.g. starch,carboxymethyl cellulose, calcium salt of carboxymethyl cellulose,hydroxypropylstarch, sodium glycole-starch, sodium bicarbonate, calciumphosphate, calcium citrate, etc.), lubricant (e.g. magnesium stearate,aerosol, talc, sodium laurylsulfate, etc.), flavoring agent (e.g. citricacid, mentol, ammonium salt of grycyrlysine, glycine, orange powders,etc.), preservative (sodium benzoate, sodium bisulfite, methylparaben,propylparaben, etc.), stabilizer (citric acid, sodium citrate, aceticacid, etc.), suspending agent (e.g. methyl cellulose,polyvinylpyrrlidione, aluminum stearate, etc.), dispersing agent [e.g.polysolbate 80, emalgen 408 (surface active agent), emasol (surfaceactive agent), etc.], aqueous diluting agent (e.g. water), base wax(e.g. cacao butter, polyethyleneglycol, witepsol, white petrolatum,etc.).

A dosage of the present active ingredient is to be varied depending onvarious factors such as weight and/or age of a patient and/or a stage ofthe allergic disease, and further the kind of administration route. Ingeneral, an effective dosage may be in a range of about 20-2000 mg/dayfor an oral route, about 2.5-250 mg/day for an intramuscular orintravenous injection, about 10-1000 mg/day for a subcutaneous injectionand about 120mg-2000 mg/day for a rectal route. The total daily amountmentioned above may be divisionally given to the patient at the intervalof 6-12 hours per day. Preferable single dose of the present activeingredient may be, for example, about 10-500 mg per tablet or capsule,about 1.25-250 mg per vial or ampoule, or about 60-500 mg persuppository, and so on, and further a pharmaceutical form for anexternal use may be, for example, about 1-10% ointment, solution oremulsion, etc.

Starting compounds to be used in the preparation of the quinazolinederivatives of this invention can be specifically prepared in thefollowing manner.

Preparation 1

A mixture of o-aminobenzonitrile (22.58 g) and formamide (96 ml) wasrefluxed for 2 hours at 220° C. After the resultant mixture was cooledto ambient temperature, precipitated crystals were separated byfiltration, washed twice with a small volume of water and dried underreduced pressure to give crystalline 4-aminoquinazoline (17.0 g).

mp: 265°-268° C.

IR (Nujol) νmax: 3100, 1690, 1615, 1585 cm⁻¹.

N.M.R. δppm (DMSO₄ -d₆): 7.4-8.0 (5H, m), 8.30 (1H, broad d, J=8.0 Hz),8.50 (1H, s).

The following compounds were prepared in substantially the same manneras that of the Preparation 1.

(1) 4-Amino-6-chloroquinazoline

mp: >270° C.

IR (Nujol) νmax: 3100, 1680, 1570, 1548 cm⁻¹.

(2) 4-Amino-7-chloroquinazoline

IR (Nujol) νmax: 3275, 3100, 1685, 1605, 1575 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 7.52 (1H, dd, J=2.0 and 8.0 Hz), 7.70 (1H, d,J=2.0 Hz), 7.90 (2H, broad s), 8.33 (1H, d, J=8.0 Hz), 8.40 (1H, s).

(3) 4-Amino-6-methylquinazoline

mp: 266°-269° C.

IR (Nujol) νmax: 3400-3100, 1680, 1580, 1555 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 2.44 (3H, s), 7.56 (4H, m), 8.05 (1H, broad s),8.30 (1H, broad s).

(4) 4-Amino-6-phenoxyquinazoline

mp: 97°-99° C.

IR (Nujol) νmax: 1664, 1642, 1590 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 6.4-7.8 (7H, m), 7.93 (1H, d, J=9.0 Hz), 8.43(1H, s), 10.4 (2H, s).

(5) 4-Amino-6-(N,N-dimethylamino)quinazoline

mp: >270° C.

IR (Nujol) νmax: 3400-3000, 1662, 1612, 1565 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 2.96 (6H, s), 7.12 (1H, d, J=3.0 Hz), 7.36 (4H,m), 8.12 (1H, s).

(6) 4-Amino-6-ethylthioquinazoline

mp: 158°-164° C.

IR (Nujol) νmax: 3300, 3100, 1670, 1600 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 1.26 (3H, t, J=8.0 Hz), 3.1 (2H, quartet, J=8.0Hz), 7.6-8.0 (4H, m), 8.2 (1H, d, J=2.0 Hz), 8.40 (1H, s).

(7) 4-Amino-7-methoxyquinazoline

IR (Nujol) νmax: 3330, 3130, 1670, 1620, 1578 1560 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 3.86 (3H, s), 7.1 (2H, m), 7.56 (2H, broad s),8.13 (1H, d, J=10.0 Hz), 8.30 (1H, s).

(8) 4-Amino-7-acetamidoquinazoline

mp: >300° C.

IR (Nujol) νmax: 1675, 1628, 1570 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 2.16 (3H, s), 7.6 (3H, broad s), 7.9-8.3 (2H, m),8.36 (1H, s), 10.23 (1H, broad s).

(9) 4-Amino-6-ethylquinazoline

mp: 224°-227° C.

IR (Nujol) νmax: 3300, 3100, 1665, 1575, 1540 cm⁻¹.

N.M.R. δppm (CDCl₃): 1.30 (3H, t, J=7.0 Hz), 1.83 (2H, s), 2.77 (2H,quartet, J=7.0 Hz), 7.4-8.0 (3H, m), 8.26 (1H, s).

(10) 4-Amino-6-butylquinazoline

mp: 209°-210° C.

IR (Nujol) νmax: 3050, 1680, 1570, 1540 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 0.7-1.8 (7H, m), 2.7 (2H, t, J=7.0 Hz), 7.63 (4H,broad s), 8.07 (1H, s), 8.37 (1H, s), 8.37 (1H, s).

(11) 4-Amino-8-methylquinazoline

mp: 200°-214° C.

IR (Nujol) νmax: 3350, 3120, 1670, 1612, 1588 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 2.66 (3H, s), 7.3-8.0 (4H, m), 8.16 (1H, d, J=9.0Hz), 8.56 (1H, s).

(12) 4-Amino-6-propylquinazoline

mp: 194°-198° C.

IR (Nujol) νmax: 3320, 3100, 1660, 1570, 1550, 1500 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 0.93 (3H, t, J=7.0 Hz), 1.3-2.1 (2H, m), 2.73(2H, t, J=7.0 Hz), 7.70 (2H, s), 7.75 (2H, m), 8.13 (1H, s), 8.46 (1H,s).

(13) 4-Amino-6,7-dimethylquinazoline

mp: >360° C.

IR (Nujol) νmax: 3270, 3070, 1680, 1620, 1560 cm⁻¹.

(14) 4-Amino-7-methylquinazoline

mp: 278°-279° C.

IR (Nujol) νmax: 3330, 3150, 1670, 1620, 900, 790 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 2.43 (3H, s), 7.3 (1H, d, J=8.0 Hz), 7.45 (1H,s), 7.6 (2H, s), 8.1 (1H, d, J=8.0 Hz), 8.33 (1H, s).

(15) 4-Amino-6-(4-methylpiperazinyl)quinazoline

mp: 229°-234° C.

IR (Nujol) νmax: 3170, 3050, 1670, 1640, 1620 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 2.23 (3H, s), 2.5 (4H, m), 3.26 (4H, m), 3.45(2H, s), 7.3-7.6 (3H, m), 8.2 (1H, s).

(16) 4-Amino-6,7-dimethoxyquinazoline

mp: 204°-206° C.

IR (Nujol) νmax: 3320, 1672, 1612, 1580 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 3.90 (6H, s), 7.1 (1H, s), 7.40 (2H, s), 7.6 (1H,s), 8.27 (1H, s).

(17) 4-Amino-6-[bis(2-hydroxyethyl)amino]quinazoline

N.M.R. δppm (DMSO-d₆): 3.53 (8H, m), 4.5 (2H, s), 7.0-7.6 (5H, m), 8.1(1H, s).

IR (Nujol) νmax: 3380, 1660, 1618, 1575 cm⁻¹.

mp: 227°-231° C.

(18) 4-Amino-7-pivalamidoquinazoline

mp: 305°-307° C.

Preparation 2

A mixture of 2-amino-5-nitrobenzonitrile (48.9 g), anhydrous potassiumcarbonate (45.6 g), formamide (240 ml) and N,N-dimethylformamide (200ml) was stirred for 50 minutes at 150° C. and then cooled to ambienttemperature. To the resultant mixture was added a small volume of waterwith stirring. Precipitated crystals were separated by filtration,washed three times with water and dried under reduced pressure to givecrystalline 4-amino-6-nitroquinazoline (50.1 g).

mp: >360° C.

IR (Nujol) νmax: 3350, 3200, 1680, 1620 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 7.76 (1H, d, J=9.0 Hz), 8.43 (1H, dd, J=3.0 and9.0 Hz), 9.26 (1H, d, J=3.0 Hz), 8.30 (2H, m).

Preparation 3

(a) A mixture of 2,4-quinazolinedione (20 g), tri-n-propylamine (38 g)and phosphorus oxychloride (200 ml) was stirred for 40 minutes at 120°C. The resultant mixture was concentrated under reduced pressure to givea solid residue, which was extracted twice with warm 2%tri-n-propylamine-heptane solution (250 ml) and twice with 2%tri-n-propylamine-ether solution (250 ml). To the combined extracts wasadded a small volume of benzene to dissolve precipitated crystals. Thesolution was washed with 0.5 N sodium hydroxide aqueous solution, threetimes with water and with aqueous solution saturated with sodiumchloride. The resultant solution was dried over anhydrous magnesiumsulfate and concentrated under reduced pressure to give crystalline2,4-dichloroquinazoline (20 g). After the crystals were dissolved indioxane (140 ml), ammonia was passed through the resultant solution for40 minutes and the resultant mixture was allowed to stand overnight.Precipitates were separated by filtration, washed twice with water anddried under reduced pressure to give crystalline2-chloro-4-aminoquinazoline (12.4 g).

(b) To the solution of sodium metal (0.7 g) in dried allylalcohol (90ml) was added 4-amino-2-chloroquinazoline (3.5 g) and the mixture wasstirred for 5 hours at 100° C. After the resultant mixture wasconcentrated under reduced pressure, to the residue was added a smallvolume of water. The aqueous mixture was extracted twice with ethylacetate. The organic layer was washed with water and with aqueoussolution saturated with sodium chloride, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure to give a crystallineresidue, which was recrystallized from a mixture of ethyl acetate andhexane to give crystalline 2-allyloxy-4-aminoquinazoline (2.8 g).

mp: 105°-110° C.

IR (Nujol) νmax: 3300, 3100, 1670, 1635, 1615 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 4.88 (2H, d, J=4.0 Hz), 5.2-5.5 (2H, m), 6.1 (1H,m), 7.2-8.3 (6H, m).

Preparation 4

(a) A mixture of 1-methylquinazoline-2,4-dione (8.8 g),tri-n-propylamine (8.6 g) and phosphorus oxychloride (80 ml) was stirredfor 1 hour at 110°-120° C. The resultant mixture was cooled to ambienttemperature and concentrated under reduced pressure to give a residue,which was dissolved in 2% tri-n-propylamine-chloroform solution. Thesolution was added dropwise to a mixture of 2 N sodium hydroxide aqueoussolution and ice at alkaline pH. The aqueous layer was separated andextracted twice with chloroform. The combined chloroform layer waswashed with water and with aqueous solution saturated with sodiumchloride, dried over anhydrous magnesium sulfate and concentrated underreduced pressure to give crystalline4-chloro-1-methyl-1H-quinazoline-2-one.

(b) A solution of 4-chloro-1-methyl-1H-quinazoline-2-one obtained abovein methanol (50 ml) and dioxane (70 ml) was ice-cooled. After ammoniawas passed through the solution for 16 minutes, the resultant solutionwas allowed to stand overnight at ambient temperature. Insolublematerials were filtered off and washed with methanol. The combinedfiltrate and washings was concentrated under reduced pressure to give aresidue, which was dissolved in methanol. To the solution was dropwiseadded ether to give precipitates, which was separated by filtration andwashed with a mixture of methanol and ether to give crystalline4-amino-1-methyl-1H-quinazoline-2-one (4.05 g). The same crystallinecompound (0.7 g) was recovered from the mother liquor in the same manneras mentioned above.

mp: 252°-262° C.

IR (Nujol) νmax: 3350, 3160, 1708, 1652, 1590, 1530 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 3.48 (3H, s), 3.50 (2H, broad s), 7.12-7.40 (2H,m), 7.72 (1H, t, J=8.0 Hz), 8.16 (1H, d, J=8.0 Hz).

Preparation 5

(a) A mixture of 2-bromo-4-ethylaniline (29.2 g) and cuprous cyanide(14.4 g) in dry pyridine (25.4 g) was stirred for 16 hours at 160° C.After cooling to 60° C., the resultant mixture was poured into a mixture(250 ml) of conc. aqueous ammonia and water (1:1) with stirring. To theresultant mixture was added ethyl acetate (300 ml) with stirring.Insoluble materials were filtered off. The organic layer was washedthree times with water and with aqueous solution saturated with sodiumchloride, dried over anhydrous magnesium sulfate and concentrated underreduced pressure to give an oily residue, to which was added benzene andconcentrated under reduced pressure. These operations were repeatedtwice to remove pyridine. The resultant oily residue was subjected to acolumn chromatography using silica gel (developing solvent: a mixture ofbenzene and hexane (3:1)) to give 2-amino-4-ethylbenzonitrile (16.4 g).

IR (film) νmax: 3460, 3370, 3225, 2200, 1620 cm⁻¹.

N.M.R. δppm (CCl₄): 1.16 (3H, t, J=7.0 Hz), 2.5 (2H, quartet, J=7.0 Hz),4.36 (2H, s), 6.5 (1H, d, J=10.0 Hz), 7-7.4 (2H, m).

(b) To a solution of 2-amino-4-ethylbenzonitrile (39.9 g) in acetic acid(200 ml) was added potassium cyanate (24.4 g) under ice-cooling in thecourse of 15 minutes and stirred overnight in water bath. To theresultant mixture was added water to give precipitates, which wereseparated by filtration, washed with water and dried at ambienttemperature. The resultant crude crystals were recrystallized fromethanol to give crystalline (2-cyano-4-ethylphenyl)urea (29.0 g).

mp: >360° C.

IR (Nujol) νmax: 3450, 3350, 3250, 3200, 2220, 1660, 1620 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 1.2 (3H, t, J=7.0 Hz), 2.6 (2H, quartet, J=7.0Hz), 6.40 (2H, broad s), 7.40-7.73 (2H, m), 8.0 (1H, d, J=8.0 Hz), 8.50(1H, broad s).

(c) To a solution of sodium metal (0.365 g) in dried methanol (300 ml)was added (2-cyano-4-ethylphenyl)urea (10 g) and the reaction mixturewas heated under reflux for 5 hours and a half. The resultant mixturewas concentrated under reduced pressure to give a residue, to which wasadded water. The resultant crystals were separated by filtration, washedwith water and dried under reduced pressure to give crystalline4-amino-6-ethyl-2-hydroxyquinazoline (9.35 g).

mp: >350° C.

IR (Nujol) νmax: 3360, 3100, 1670, 1635, 1600 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 1.2 (3H, t, J=8.0 Hz), 2.6 (2H, quartet, J=8.0Hz), 7.06 (1H, d, J=8.0 Hz), 7.46 (1H, dd, J=2.0 and 8.0 Hz), 7.6-8.0(3H, m), 11.2 (1H, s).

Preparation 6

A mixture of 2-amino-5-ethylbenzoic acid (20.28 g) and ethylchlorocarbonate (53.5 g) was stirred for 50 minutes at 100° C. and thencooled to 90° C. To the mixture was added dropwise acetyl chloride(13.81 g) in the course of 15 minutes and the reaction mixture wasstirred for 2 hours at 100° C. After the resultant mixture was cooled toambient temperature, to the mixture was added hexane and allowed tostand at ambient temperature to give crystals, which were separated byfiltration, washed with hexane and dried under reduced pressure to givecrystalline 6-ethyl-2H-3,1-benzoxazine-2,4(1H)-dione (19.55 g).

mp: 178°-181° C.

IR (Nujol) νmax: 3230, 1760, 1690, 1615, 1605 cm⁻¹.

N.M.R. δppm (CDCl₃): 1.23 (3H, t, J=8.0 Hz), 2.7 (2H, quartet, J=8.0Hz), 7.0-8.0 (3H, m), 9.3 (1H, s).

(b) A mixture of 6-ethyl-2H-3,1-benzoxazine-2,4(1H)-dione (19.55 g) andurea (6.18 g) in dry N,N-dimethylformamide (98 ml) was heated underreflux for 3 hours and 40 minutes. After the reaction mixture was cooledto ambient temperature, to the mixture was added water with stirring togive crystals, which were separated by filtration, washed with water anddried under reduced pressure to give crystalline6-ethyl-1H,3H-quinazoline-2,4-dione (11.74 g).

mp: 271°-274° C.

IR (Nujol) νmax: 3310, 3160, 3030, 1720, 1685, 1620 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 1.2 (3H, t, J=8.0 Hz), 2.65 (2H, quartet, J=8.0Hz), 7.18 (1H, d, J=8.0 Hz), 7.56 (1H, dd, J=2.0 and 8.0 Hz), 7.8 (1H,d, J=2.0 Hz), 12.0 (2H, s).

(c) A mixture of 6-ethyl-1H,3H-quinazoline-2,4-dione (3.78 g),tri-n-propylamine (5.72 g) and phosphorus oxychloride (38 ml) wasstirred for 40 minutes at 120° C. and then cooled to ambienttemperature. The reaction mixture was concentrated under reducedpressure to give a residue, to which was added warm (50°-60° C.) 2%tri-n-propylamine-heptane solution (50 ml) with stirring. Thesupernatant was separated and the solid residue was treated three timesin substantially same manner as mentioned above. To the combined heptanelayer was added benzene. The resultant mixture was washed twice with 5%sodium hydroxide aqueous solution (50 ml), three times with water andwith aqueous solution saturated with sodium chloride. The mixture wasdried over anhydrous magnesium sulfate and concentrated under reducedpressure to give crystalline. 2,4-dichloro-6-ethylquinazoline (4.07 g).

mp: 80°-83° C.

IR (Nujol) νmax: 1530, 1480, 1450, 1410, 1160, 1110 cm⁻¹.

N.M.R. δppm (CDCl₃): 1.4 (3H, t, J=8.0 Hz), 2.93 (2H, quartet, J=8.0Hz), 7.96 (2H, broad s), 8.1 (1H, s).

(d) A solution of 2,4-dichloro-6-ethylquinazoline (10.8 g) in methanoland chloroform (70 ml ) was cooled with ice-water. Ammonia was passedthrough the reaction mixture for 20 minutes and the mixture was allowedto stand for 18 hours at ambient temperature. The resultant mixture wasconcentrated under reduced pressure to give a residue, to which wasadded water and heated to 50°-60° C. with stirring. The precipitates wasseparated by filtration, washed with hot water and recrystallized fromdioxane to give crystalline 4-amino-2-chloro-6-ethylquinazoline (8.3 g).Crystals (0.7 g) of the same compound were obtained by treating themother liquor in substantially the same manner as mentioned above.

mp: 244°-246° C.

IR (Nujol) νmax: 3380, 3340, 3120, 1660, 1570, 1540 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 1.3 (3H, t, J=8.0 Hz), 2.8 (2H, quartet, J=8.0Hz), 7.5-7.9 (2H, m), 8.16 (1H, s), 8.3 (2H, broad s).

(e) To a solution of sodium metal (1.19 g) in methanol (270 ml) wasadded 4-amino-2-chloro-6-ethylquinazoline (9.01 g). The reaction mixturewas heated under reflux for 7 hours and heated for 38 hours at 60° C.The resultant mixture was concentrated under reduced pressure to give aresidue, to which was added water under warming with stirring. Theprecipitates were separated by filtration and dried under reducedpressure to give crystalline 4-amino-6-ethyl-2-methoxyquinazoline (6.77g).

mp: 168°-170° C.

IR (Nujol) νmax: 3300, 1630, 1580 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 1.30 (3H, t, J=7.0 Hz), 2.76 (2H, quartet, J=7.0Hz), 4.06 (3H, s), 7.70 (2H, m), 8.36 (1H, broad s), 9.20 (2H, m).

Preparation 7

A mixture of iron (113.9 g), conc. hydrochloric acid (57 ml) and water(2.3 liters) was stirred at 95° C. for 20 minutes. To the mixture wasadded during 10 minutes 4-amino-6-nitroquinazoline (114.1 g). Thereaction mixture was stirred at 95° C. for an hour and a half and thenfiltered. The filter cake was washed with hot water. The combinedfiltrate and washings were concentrated under reduced pressure to give aresidue, to which was added a small volume of ethanol to giveprecipitates. The precipitates were separated by filtration and dried togive 4,6-diaminoquinazoline hydrochloride (94.8 g). The same compound(4.3 g) was recovered from the mother liquor in the same manner asmentioned above.

IR (Nujol) νmax: 3310, 1665, 1610, 1560 cm⁻¹.

Preparation 8

A mixture of 4,6-diaminoquinazoline hydrochloride (1.97 g), sodiumhydrogen carbonate (6.72 g) and pyridine (20 ml) was stirred underice-cooling. To the mixture was added dropwise during 30 minutesmethanesulfonyl chloride (4.58 g) under ice-cooling. The reactionmixture was stirred for an hour under ice-cooling and for 4 hours atambient temperature. To the mixture was added ice-water. The resultantmixture was stirred for about five minutes and concentrated underreduced pressure. To the residue was added a mixture of chloroform andmethanol. The mixture was stirred under heating. Insoluble materialswere removed by filtration and then the filtrate was concentrated underreduced pressure to give crude crystals, to which was added a mixture ofchloroform and methanol (4:1). The mixture was stirred under heating togive crystals, which were separated by filtration to give crystalline4-amino-6-methanesulfonamidoquinazoline (1.45 g).

mp: 287°-290° C.

IR (Nujol) νmax: 3350, 3150, 1660, 1615 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 3.3 (3H, s), 7.7-8.33 (4H, m), 8.83 (1H, s), 9.8(2H, s).

Preparation 9

To a mixture of 4,6-diaminoquinazoline hydrochloride (10.0 g),tripropylamine (17.61 g) and dry pyridine (100 ml) was added dropwiseduring 35 minutes 3,3-dimethylbutyryl chloride (10.34 g) underice-cooling. The reaction mixture was stirred for 2 hours at the sametemperature. To the resultant mixture was added ice-water. The mixturewas stirred for 5 minutes and then concentrated under reduced pressure.To the residue was added water and sodium hydrogen carbonate (13.0 g)little by little to give precipitates, which were separated byfiltration, washed with water and dried. Thus obtained crude crystalswere dissolved in a mixture of chloroform and methanol under heating.After insoluble materials were removed by filtration, the filtrate wasconcentrated under reduced pressure to give a residue, which wassuspended in 5% methanol-chloroform solution (70 ml). After stirringunder heating, the suspension was filtered to give crystalline4-amino-6-(3,3-dimethylbutyramido)quinazoline (8.5 g).

mp: 273°-274° C.

IR (Nujol) νmax: 3330, 3220, 1685, 1650 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 1.06 (9H, s), 2.26 (2H, s), 7.6 (2H, s), 7.63(1H, d, J=8.0 Hz), 7.83 (1H, dd, J=2.0 and 8.0 Hz), 8.4 (1H, s), 8.4(1H, d, J=2.0 Hz), 10.03 (1H, s).

Preparation 10

The following compounds were prepared in substantially the same manneras that of Preparation 9.

(1) 4-Amino-6-pivalamidoquinazoline

mp: 269°-273° C.

IR (Nujol) νmax: 3325, 3175, 1670, 1580, 1560, 1525 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 1.23 (9H, s), 7.5 (2H, s), 7.56 (1H, d, J=9.0Hz), 7.80 (1H, dd, J=2.0 and 9.0 Hz), 8.3 (1H, s), 8.35 (1H, s), 9.4(1H, s).

(2) 4-Amino-6-(2,3-dimethylpentanamido)quinazoline

mp: 240°-243° C.

Preparation 11

To a mixture of 4,6-diaminoquinazoline hydrochloride (1.97 g),tripropylamine (2.60 g) and dry pyridine (20 ml) in an ice-bath wasadded dropwise during 10 minutes 2-ethylbutyryl chloride (1.75 g). Themixture was stirred for 3 hours at the same temperature. Crushed ice wasadded to the reaction mixture. The mixture was stirred for 5 minutes andconcentrated under reduced pressure. After the addition of water (50ml), sodium hydrogen carbonate (3.36 g) was added in small portions tothe residue to give precipitates which were separated by filtration,washed with water and dried. The crude crystals were dissolved in amixture of chloroform and methanol under heating. After insolublematerials were removed by filtration, the filtrate was concentratedunder reduced pressure to give a residue, which was suspended in ethylacetate. After stirring under heating, the suspension was filtered togive crystalline 4-amino-6-(2-ethylbutyramido)quinazoline (1.20 g).

mp. 248°-250° C.

IR (Nujol) νmax: 3320, 3100, 1660, 1570, 1535 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 9.2 (6H, t, J=6.0 Hz), 1.34-1.88 (4H, m),2.08-2.44 (1H, m), 7.2 (2H, s), 7.6 (1H, d, J=10.0 Hz), 7.8 (1H, dd,J=3.0, 10.0 Hz), 8.34 (1H, s), 8.38 (1H, d, J=3.0 Hz), 10.02 (1H, s).

Preparation 12

A mixture of 4,6-diaminoquinazoline hydrochloride (10 g) andtripropylamine (17.6 g) in dry pyridine (100 ml) was stirred in anice-bath for 1 hour. To the mixture was added dropwise during 40 minutesisobutyric anhydride (8.85 g). The mixture was stirred for 1 hour at 5°C. Crushed ice was added to the reaction mixture. The mixture wasstirred for 5 minutes and concentrated under reduced pressure to give aresidue which was dissolved in water. After insoluble materials wereremoved by filtration, the filtrate was adjusted to pH 8-9 with aqueoussodium bicarbonate solution and concentrated under reduced pressure togive a residue which was dissolved in a mixture of chloroform andmethanol. The solution was filtered and concentrated under reducedpressure to give a crystalline residue which was suspended in ethylacetate. The suspension was filtered to give4-amino-6-(2-methylpropionamido)quinazoline (5.05 g).

mp. 280°-283° C.

IR (Nujol) νmax: 3260, 3120, 1655, 1575, 1510 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 1.12 (6H, d, J=7.0 Hz), 2.5-2.8 (1H, m), 7.5 (2H,s), 7.5 (1H, d, J=9.0 Hz), 7.85 (1H, dd, J=2.0, 9.0 Hz), 8.3 (1H, s),8.4 (1H, d, J=2.0 Hz), 10.03 (1H, s).

Preparation 13

A mixture of 4,6-diaminoquinazoline hydrochloride (12 g) andtripropylamine (31.7 g) in dry pyridine (120 ml) was stirred in anice-bath for 1 hour. Cyclohexanecarbonyl chloride (12.1 g) was addeddropwise during 4 hours and 20 minutes to the mixture at 70° C. Themixture was stirred for additional 1 hour at 5° C. Crushed ice was addedto the reaction mixture. The mixture was stirred for 1 hour andconcentrated under reduced pressure. After addition of water, themixture was adjusted to pH 8 with sodium hydrogen carbonate to giveprecipitates which were separated by filtration, washed with water anddried. The precipitates were dissolved in a mixture of chloroform andmethanol under heating. Insoluble materials were removed by filtration.The filtrate was concentrated under reduced pressure to give crystalline4-amino-6-cyclohexanecarboxamidoquinazoline (9.25 g).

mp. 301°-303° C.

IR (Nujol) νmax: 3700-3100, 1650, 1585, 1560, 1510 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 1.0-2.0 (10H, m), 2.4-2.8 (1H, m), 7.53 (2H, s),7.6 (1H, d, J=8.0 Hz), 7.78 (1H, dd, J=2.0, 8.0 Hz), 8.3 (1H, s), 8.43(1H, d, J=2.0 Hz), 10.0 (1H, s).

Preparation 14

A mixture of 4,6-diaminoquinazoline hydrochloride (10 g) andtripropylamine (26.4 g) in dry pyridine (100 ml) was stirred in anice-bath for 20 minutes. To the mixture was added dropwise during 1.5hours 3-cyclopentylpropionyl chloride (12.2 g). The mixture was stirredin an ice-bath for 1.5 hours. Crushed ice was added to the reactionmixture. The mixture was stirred for 5 minutes and concentrated underreduced pressure. After addition of water, sodium hydrogen carbonate wasadded in small portions to the mixture to give precipitates which wereseparated by filtration, washed with water and dried. The crude crystalswere dissolved in a mixture of chloroform and methanol under heating.After the filtration of insoluble materials, the filtrate was treatedwith activated charcoal and concentrated under reduced pressure to givea residue. The residue was suspended in ethyl acetate. The suspensionwas stirred for 1 hour under heating and filtered to give crystalline4-amino-6-(3-cyclopentylpropionamido)quinazoline (7.2 g).

mp. 279°-283° C.

IR (Nujol) νmax: 3280, 3120, 1660, 1565, 1510 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 0.7-2.16 (11H, m), 2.46 (2H, t, J=6.0 Hz), 7.6(2H, m), 7.66 (1H, d, J=9.0 Hz), 7.93 (1H, d, J=9.0 Hz), 8.33 (1H, s),8.50 (1H, s), 10.40 (1H, s).

The following Examples are given for the purpose of illustrating thisinvention.

EXAMPLE 1

A mixture of 4-aminoquinazoline (11.6 g) and diethylethoxymethylenepropanedioate (19.0 g) in N,N-dimethylformamide (40 ml)was stirred for 1 hour and 20 minutes at 160° C. and then cooled to 0°C. to precipitate crystals. To the mixture was added small volume ofwater with stirring. The crystals were separated by filtration, washedwith water, dried overnight under reduced pressure and dissolved inethyl acetate. The resultant solution was dried over anhydrous magnesiumsulfate and recrystallized from a mixture of ethyl acetate and hexane togive crystalline diethyl[(4-quinazolinylamino)methylene]propanedioate(22.7 g).

mp: 115°-117° C.

IR (Nujol) νmax: 1735, 1660, 1628 cm⁻¹.

N.M.R. δppm (CDCl₃): 1.36 (3H, t, J=7.0 Hz), 1.40 (3H, t, J=7.0 Hz),4.36 (4H, m), 7.5-8.2 (4H, m), 8.96 (1H, s), 9.40 (1H, d, J=12.0 Hz),12.3 (1H, broad d, J=12 Hz).

EXAMPLE 2

The following compounds were prepared in substantially the same manneras that of Example 1.

(1) Diethyl [(6-phenoxy-4-quinazolinylamino)methylene]propanedioate

mp: 121°-123° C. (recrystallized from a mixture of chloroform, ethylacetate and hexane).

IR (Nujol) νmax: 1720, 1625, 1617, 1608, 1580 cm⁻¹.

N.M.R. δppm (CDCl₃): 1.40 (6H, t, J=8.0 Hz), 4.33 (2H, quartet, J=8.0Hz), 4.37 (2H, quartet, J=8.0 Hz), 7.0-7.6 (7H, m), 8.06 (1H, d, J=9.0Hz), 8.90 (1H, s), 9.33 (1H, d, J=12.0 Hz), 12.16 (1H, d, J=12.0 Hz).

(2) Diethyl[(6-dimethylamino-4-quinazolinylamino)methylene]propanedioate

mp: 156°-158° C. (recrystallized from a mixture of chloroform andhexane).

IR (Nujol) νmax: 1720, 1652, 1628, 1600 cm⁻¹.

N.M.R. δppm (CDCl₃): 1.36 (6H, m), 3.04 (6H, s), 4.34 (4H, m), 6.50 (1H,d, J=3.0 Hz), 7.34 (1H, dd, J=3.0 and 9.0 Hz), 7.72 (1H, d, J=9.0 Hz),8.60 (1H, s), 9.24 (1H, d, J=11.0 Hz), 11.90 (1H, d, J=11.0 Hz).

(3) Diethyl [(6-ethylthio-4-quinazolinylamino)methylene]propanedioate

mp: 103°-106° C. (recrystallized from a mixture of ethyl acetate andhexane).

IR (Nujol) νmax: 1722, 1650, 1624, 1600 cm⁻¹.

N.M.R. δppm (CDCl₃): 1.3-1.8 (9H, m), 3.14 (2H, quartet, J=8.0 Hz),4.2-4.7 (4H, m), 7.7-8.1 (3H, m), 8.90 (1H, s), 9.3 (1H, d, J=12.0 Hz),12.4 (1H, d, J=12.0 Hz).

(4) Diethyl [(7-methoxy-4-quinazolinylamino)methylene]propanedioate

mp: 134°-138° C. (recrystallized from a mixture of ethyl acetate andhexane).

IR (Nujol) νmax: 1736, 1630, 1572 cm⁻¹.

N.M.R. δppm (CDCl₃): 1.40 (3H, t, 7.0 Hz), 1.43 (3H, t, J=7.0 Hz), 3.96(3H, s), 4.36 (4H, m), 7.1-7.4 (2H, m), 7.83 (1H, d, J=9.0 Hz), 8.87(1H, s), 9.30 (1H, d, J=12.0 Hz), 12.2 (1H, d, J=12.0 Hz).

(5) Diethyl [(7-acetamido-4-quinazolinylamino)methylene]propanedioate

IR (Nujol) νmax: 3420, 1720, 1695, 1655, 1630, 1585 cm⁻¹.

N.M.R. δppm (CDCl₃ -DMSO-d₆): 1.36 (3H, t, J=7.0 Hz), 1.43 (3H, t, J=7.0Hz), 2.23 (3H, s), 4.30 (4H, m), 7.93 (2H, m), 8.34 (1H, m), 8.90 (1H,s), 9.30 (1H, d, J=12 Hz), 10.27 (1H, s), 12.2 (1H, d, J=12 Hz).

(6) Diethyl [(2-hydroxy-4-quinazolinylamino)methylene]propanedioate

mp: 265°-268° C. (recrystallized from a mixture of N,N-dimethylformamideand water).

IR (Nujol) νmax: 1702, 1660, 1630, 1585, 1575 cm⁻¹.

N.M.R. δppm (CDCl₃): 1.40 (6H, m), 4.40 (4H, m), 7.3-8.0 (4H, m), 9.24(1H, d, J=11.0 Hz), 12.3 (1H, d, J=11.0 Hz), 12.90 (1H, s).

(7) Diethyl [(2-methoxy-4-quinazolinylamino)methylene]propanedioate

mp: 129°-135° C. (recrystallized from a mixture of ethyl acetate andhexane).

IR (Nujol) νmax: 1692, 1645, 1630, 1608, 1568 cm⁻¹.

N.M.R. δppm (CDCl₃): 1.40 (3H, t, J=7.0 Hz), 1.46 (3H, t, J=7.0 Hz),4.16 (3H, s), 4.32 (4H, m), 7.3-8.0 (4H, m), 9.30 (1H, d, J=11.0 Hz),12.3 (1H, d, J=11.0 Hz).

(8) Diethyl [(2-allyloxy-4-quinazolinylamino)methylene]propanedioate

mp: 117°-119° C. (recrystallized from a mixture of ethyl acetate andhexane).

IR (Nujol) νmax: 1672, 1640, 1620, 1560 cm⁻¹.

N.M.R. δppm (CDCl₃): 1.40 (3H, t, J=7.0 Hz), 1.45 (3H, t, J=7.0 Hz),4.40 (4H, m), 5.0-6.5 (5H, m), 7.3-8.0 (4H, m), 9.30 (1H, d, J=12.0 Hz),12.3 (1H, d, J=12.0 Hz).

(9) Diethyl [(2-methyl-4-quinazolinylamino)methylene]propanedioate

IR (Nujol) νmax: 1680, 1640, 1620, 1600, 1550 cm⁻¹.

N.M.R. δppm (CDCl₃): 1.40 (6H, m), 2.76 (3H, s), 4.33 (4H, m), 7.44-8.0(4H, m), 9.34 (1H, d, J=12.0 Hz), 12.14 (1H, d, J=12.0 Hz).

(10) Diethyl[(2-dimethylamino-4-quinazolinylamino)methylene]propanedioate

mp: 126°-128° C. (recrystallized from ethanol).

IR (Nujol) νmax: 3250, 1695, 1640, 1610, 1565 cm⁻¹.

N.M.R. δppm (CDCl₃): 1.40 (6H, m), 3.26 (6H, s), 4.37 (4H, m), 7.0-7.77(4H, m), 9.27 (1H, d, J=12 Hz), 11.90 (1H, d, J=12 Hz).

(11) Diethyl[(2-hydroxy-6-ethyl-4-quinazolynylamino)methylene]propanedioate

mp: 267°-270° C. (recrystallized from a mixture of chloroform andmethanol).

IR (Nujol) νmax: 1720, 1665, 1615, 1588 cm⁻¹.

N.M.R. δppm (CDCl₃): 1.16-1.76 (9H, m), 2.83 (2H, quartet, J=8.0 Hz),4.30 (4H, m), 7.56 (3H,broad s), 9.26 (1H, d, J=11.5 Hz), 12.26 (1H, d,J=11.5 Hz), 12.90 (1H, s).

(12) Diethyl[(2-methoxy-6-ethyl-4-quinazolinylamino)methylene]propanedioate

mp: 149°-152° C. (recrystallized from ethyl acetate).

IR (Nujol) νmax: 1730, 1652, 1635, 1622, 1575 cm⁻¹.

N.M.R. δppm (CDCl₃): 1.20-1.67 (9H, m), 2.86 (2H, quartet, J=8.0 Hz),4.17 (3H, s), 4.36 (4H, m), 7.63 (3H, m), 9.23 (1H, d, J=11.5 Hz), 12.16(1H, d, J=11.5 Hz).

EXAMPLE 3

A mixture of 4-amino-6-ethylquinazoline (6.35 g) and diethylethoxymethylenepropanedioate (9.52 g) in N,N-dimethylformamide (25 ml)was stirred for 3 hours at 110° C. and then cooled to ambienttemperature. A small volume of water was added to the resultant mixtureto precipitate crystals, which were separated by filtration and washedwith water. The crystals were dissolved in chloroform, washed with anaqueous solution saturated with sodium chloride, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure to give acrystalline residue, which was recrystallized from a mixture of ethylacetate and hexane to give crystalline diethyl[(6-ethyl-4-quinazolinylamino)methylene]propanedioate (8.40 g). Further,crystals (2.75 g) of the same compound were recovered from the motherliquor in the same manner as mentioned above.

mp: 104°-106° C.

IR (Nujol) νmax: 3250, 1700, 1645, 1610, 1560 cm⁻¹.

N.M.R. δppm (CDCl₃): 1.2-1.5 (9H, m), 2.96 (2H, quartet, J=7.0 Hz),4.1-4.7 (4H, m), 7.7-8.1 (3H, m), 8.95 (1H, s), 9.4 (1H, d, J=12.0 Hz),12.3 (1H, d, J=12.0 Hz).

EXAMPLE 4

The following compounds were prepared in substantially the same manneras that of Example 3.

(1) Diethyl [(6-methyl-4-quinazolinylamino)methylene]propanedioate

mp: 137°-139° C. (recrystallized from a mixture of chloroform andhexane).

Ir (Nujol) νmax: 1735, 1655, 1630, 1615 cm⁻¹.

N.M.R. δppm (CDCl₃): 1.40 (3H, t, J=8.0 Hz), 1.46 (3H, t, J=8.0 Hz),2.63 (3H, s), 4.33 (2H, quartet, J=8.0 Hz), 4.46 (2H, quartet, J=8.0Hz), 7.8-8.1 (3H, m), 8.93 (1H, s), 9.4 (1H, d, J=12.0 Hz), 12.16 (1H,d, J=12.0 Hz).

(2) Diethyl [(6-butyl-4-quinazolinylamino)methylene]propanedioate

mp: 83°-85° C. (recrystallized from a mixture of ethyl acetate andhexane).

IR (Nujol) νmax: 3220, 1730, 1650, 1630, 1610, 1560 cm⁻¹.

N.M.R. δppm (CCl₄): 0.7-2.1 (13H, m), 2.86 (2H, t, J=7.0 Hz), 4.26 (2H,quartet, J=7.0 Hz), 4.36 (2H, quartet, J=7.0 Hz), 7.6-8.0 (3H, m), 8.76(1H, s), 9.23 (1H, d, J=12.0 Hz), 12.2 (1H, d, J=12.0 Hz).

(3) Diethyl [(8-methyl-4-quinazolinylamino)methylene]propanedioate

mp: 121°-123° C. (recrystallized from a mixture of ethyl acetate andhexane).

IR (Nujol) νmax: 1705, 1650, 1618, 1605, 1580 cm⁻¹.

N.M.R. δppm (CDCl₃): 1.40 (3H, t, J=7.0 Hz), 1.43 (3H, t, J=7.0 Hz),2.73 (3H, s), 4.37 (4H, m), 7.4-7.9 (3H, m), 8.97 (1H, s), 9.33 (1H, d,J=12.0 Hz), 12.26 (1H, d, J=12.0 Hz).

(4) Diethyl ](6-propyl-4-quinazolinylamino)methylene]propanedioate

mp: 96°-99° C. (recrystallized from a mixture of ethyl acetate andhexane).

IR (Nujol) νmax: 3200, 1690, 1640, 1630, 1600, 1550 cm⁻¹.

N.M.R. δppm (CCl₄): 0.8-2.2 (11H, m), 2.9 (2H, t, J=8.0 Hz), 4.0-4.7(4H, m), 7.5-8.0 (3H, m), 8.8 (1H, s), 9.23 (1H, d, J=12 Hz), 12.23 (1H,d, J=12.0 Hz).

(5) Diethyl [(7-methyl-4-quinazolinylamino)methylene]propanedioate

mp: 118°-120° C. (recrystallized from a mixture of chloroform andhexane).

IR (Nujol) νmax: 3250, 1685, 1640, 1620, 1605, 1560 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 1.2 (3H, t, J=7.0 Hz), 1.26 (3H, t, J=7.0 Hz),3.2 (3H, s), 4.15 (2H, quartet, J=7.0 Hz), 4.26 (2H, quartet, J=7.0 Hz),7.4-8.0 (3H, m), 8.8 (1H, s), 9.06 (1H, d, J=12.0 Hz), 11.53 (1H, d,J=12.0 Hz).

(6) Diethyl[(6-{bis(2-hydroxyethyl)amino}-4-quinazolinylamino]methylene]propanedioate

mp: 194°-195° C. (recrystallized from chloroform).

IR (Nujol) νmax: 3300, 1720, 1648, 1630, 1605 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 1.30 (3H, t, J=7.0 Hz), 1.33 (3H, t, J=7.0 Hz),3.60 (8H, m), 4.26 (4H, m), 4.80 (2H, m), 6.73 (1H, broad s), 7.7 (2H,m), 8.63 (1H, s), 9.16 (1H, d, J=12.0 Hz), 11.56 (1H, d, J=12.0 Hz).

EXAMPLE 5

A mixture of 4-amino-6-(4-methylpiperazinyl)quinazoline (2.19 g) anddiethyl ethoxymethylenepropanedioate (2.13 g) in isobutylalcohol (9 ml)was stirred for 2 hours and 25 minutes at 100° C. and then cooled toambient temperature. The resultant mixture was concentrated underreduced pressure to give a residue, which was recrystallized fromethanol to give crystalline diethyl[{6-(4-methylpiperazinyl)-4-quinazolinylamino}methylene]propanedioate(1.58 g).

mp: 154°-159° C.

IR (Nujol) νmax: 3300, 1760, 1740, 1690, 1650, 1630, 1600 cm⁻¹.

N.M.R. δppm (CDCl₃): 1.40 (3H, t, J=7.0 Hz), 1.43 (3H, t, J=7.0 Hz),2.40 (3H, s), 2.63 (4H, m), 3.43 (4H, m), 4.33 (4H, m), 7.0 (1H, d,J=3.0 Hz), 7.56 (1H, dd, J=3.0 and 9.0 Hz), 7.86 (1H, d, J=9.0 Hz), 8.76(1H, s), 9.30 (1H, d, J=12.0 Hz).

EXAMPLE 6

The following compound was prepared by substantially the same manner asthat of Example 5.

Diethyl [(6,7-dimethoxy-4-quinazolinylamino)methylene]propanedioate

mp: 226°-229° C. (recrystallized from a mixture of chloroform andhexane).

IR (Nujol) νmax: 1675, 1636, 1620, 1608, 1550 cm⁻¹.

N.M.R. δppm (CDCl₃): 1.37 (3H, t, J=7.0 Hz), 1.40 (3H, t, J=7.0 Hz),4.03 (3H, s), 4.06 (3H, s), 4.33 (4H, m), 7.03 (1H, s), 7.23 (1H, s),8.76 (1H, s), 9.30 (1H, d, J=12.0 Hz), 12.0 (1H, d, J=12.0 Hz).

EXAMPLE 7

A mixture of 4-amino-1-methyl-1H-quinazoline-2-one (4.20 g) and diethylethoxymethylenepropanedioate (5.7 g) in N,N-dimethylformamide (20 ml)was stirred for 3 hours at 150° C. and then cooled to ambienttemperature. Precipitated crystals were separated by filtration, washedwith water and dried under reduced pressure to give crude crystals,which were recrystallized from a mixture of chloroform, ethyl acetateand hexane to give crystalline diethyl[(1-methyl-1H-2-oxo-4-quinazolinylamino)methylene]propanedioate (4.0 g).

mp: 182°-185° C.

IR (Nujol) νmax: 1725, 1700, 1675, 1635, 1610, 1588 cm⁻¹.

N.M.R. δppm (CDCl₃): 1.30 (3H, t, J=7.0 Hz), 1.40 (3H, t, J=7.0 Hz),3.66 (3H, s), 4.33 (4H, m), 7.2-7.5 (2H, m), 7.6-8.0 (2H, m), 9.16 (1H,d, J=12.0 Hz), 12.23 (1H, d, J=12.0 Hz).

EXAMPLE 8

A mixture of 2,4-diaminoquinazoline (3 g), diethylethoxymethylenepropanedioate (8.5 g) in N,N-dimethylformamide (15ml) wasstirred for 2 hours and 45 minutes at 150° C. and then cooled to ambienttemperature. To the resultant mixture was added a small volume of waterto give crystals, which were separated by filtration, washed with waterand dried under reduced pressure. The resultant crude crystals weresubjected to a column chromatography using silica gel (developingsolvent: a mixture of chloroform and ethyl acetate) to give crystallinetetraethyl2,2-[2,4-quinazolinediylbis(iminomethylidyne)]bispropanedioate (1.8 g).

mp: 146°-148° C.

IR (Nujol) νmax: 3250, 1700, 1680, 1650, 1640, 1630, 1600, 1545 cm⁻¹.

N.M.R. δppm (CDCl₃): 1.43 (12H, m), 4.40 (8H, m), 7.33-8.00 (4H, m),9.23 (1H, d, J=12.0 Hz), 9.25 (1H, d, J=13.0 Hz), 11.0 (1H, d, J=13.0Hz), 12.30 (1H, d, J=12.0 Hz).

EXAMPLE 9

A mixture of 4-aminoquinazoline (2.9 g) and2,2-dimethyl-5-ethoxymethylene-1,3-dioxane-4,6-dione (4.46 g) inN,N-dimethylformamide (20 ml) was stirred for 1 hour and 10 minutes at110° C. The resultant mixture was cooled to ambient temperature andallowed to stand overnight to give crystals, which were separated byfiltration and washed with a mixture of ethyl acetate and hexane to givecrystalline2,2-dimethyl-5-[(4-quinazolinyl)amino]methylene-1,3-dioxane-4,6-dione(4.1 g).

mp: 191°-193° C.

IR (Nujol) νmax: 1732, 1680, 1620, 1608 cm⁻¹.

N.M.R. δppm (CDCl₃): 1.80 (6H, s), 7.60-8.17 (4H, m), 9.03 (1H, s), 9.67(1H, d, J=12.2 Hz), 11.43 (1H, broad d, J=12.2 Hz).

EXAMPLE 10

A mixture of 4-amino-6-nitroquinazoline (57.0 g) and diethylethoxymethylenepropanedioate (130 g) in anhydrous N,N-dimethylformamide(570 ml) was cooled at 5° C. To the reaction mixture was added sodiumhydride (65.5% in mineral oil) (13.2 g) in the course of 30 minutes andthe mixture was stirred for 1 hour and 40 minutes under ice-cooling.After ammonium chloride (47.2 g) was added to the reaction mixture andstirred for 20 minutes, ice-water (1 liter) was added to the resultantmixture with stirring and allowed to stand to give crystals, which wereseparated by filtration, washed with water and dried overnight atambient temperature. The resultant crude crystals were dissolved inchloroform (1.5 liters) under heating. Insoluble materials were filteredoff and the filtrate was concentrated under reduced pressure to givecrystals, which were dissolved in methanol (300 ml) under heating andallowed to stand at ambient temperature. The resultant crystals wereseparated by filtration, washed with methanol and dried under reducedpressure to give yellowish crystalline diethyl[(6-nitro-4-quinazolinylamino)methylene]propanedioate (64.9 g).

mp: 228°-230° C.

IR (Nujol) νmax: 1715, 1640, 1618 cm⁻¹.

N.M.R. δppm (CDCl₃): 1.40 (3H, t, J=7.0 Hz), 1.46 (3H, t, J=7.0 Hz),4.33 (2H, q, J=7.0 Hz), 4.46 (2H, q, J=7.0 Hz), 8.18 (1H, d, J=9.0 Hz),8.7 (1H, dd, J=2.0 and 9.0 Hz), 8.98 (1H, d, J=2.0 Hz), 9.06 (1H, s),9.3 (1H, d, J=12.0 Hz), 12.55 (1H, d, J=12.0 Hz).

EXAMPLE 11

A mixture of 4-amino-6-chloroquinazoline (8.7 g) and diethylethoxymethylenepropanedioate (11.53 g) in N,N-dimethylformamide (25 ml)was stirred for 2 hours and 40 minutes at 150° C. After the reactionmixture was cooled to ambient temperature, to the mixture was addedwater with stirring to give crystals, which were washed with water,dried under reduced pressure and dissolved in ethyl acetate underheating. Insoluble materials were filtered off. To the filtrate wasadded hexane and allowed to stand at ambient temperature to givecrystals, which were separated by filtration and washed with a mixtureof ethyl acetate and hexane to give a mixture (13.48 g) of crystallinediethyl [(6-chloro-4-quinazolinylamino)methylene]propanedioate and ethyl10-chloro-4-oxo-4H-pyrimido[1,2-c]quinazoline-3-carboxylate.

(a) Diethyl [(6-chloro-4-quinazolinylamino)methylene]propanedioate

N.M.R. δppm (CDCl₃): 1.3-1.6 (6H, m), 4.2-4.6 (4H, m), 7.7-8.2 (3H, m),8.9 (1H, s), 9.26 (1H, d, J=11.0 Hz), 12.16 (1H, broad d, J=11.0 Hz).

(b) Ethyl 10-chloro-4-oxo-4H-pyrimido[1,2-c]quinazoline-3-carboxylate

N.M.R. δppm (CDCl₃): 1.43 (3H, t, J=7.0 Hz), 4.40 (2H, q, J=7.0 Hz),7.88 (2H, broad s), 8.70 (1H, m), 8.93 (1H, s), 9.54 (1H, s).

EXAMPLE 12

A mixture of 4-amino-7-chloroquinazoline (1.3 g) and diethylethoxymethylenepropanedioate (1.72 g) in N,N-dimethylformamide (6 ml)was stirred for 2 hours at 150° C. The resultant mixture was cooled toambient temperature and poured into ice-water to give crystals, whichwere separated by filtration, washed with water and recrystallized fromethanol to give a mixture (1.65 g) of diethyl[(7-chloro-4-quinazolinylamino)methylene]propanedioate and ethyl9-chloro-4-oxo-4H-pyrimido[1,2-c]quinazoline-3-carboxylate. The mixturewas subjected to a column chromatography using silica gel (developingsolvent: a mixture of benzene and ethyl acetate (10:1)) to give purifiedcrystals.

(a) Diethyl [(7-chloro-4-quinazolinylamino)methylene]propanedioate

N.M.R. δppm (CDCl₃): 1.42 (6H, m), 4.35 (4H, m), 7.56 (1H, dd, J=2.0 and8.0 Hz), 7.90 (1H, d, J=8.0 Hz), 7.97 (1H, broad s), 8.90 (1H, s), 9.27(1H, d, J=12.0 Hz), 12.26 (1H, d, J=12.0 Hz).

(b) Ethyl 9-chloro-4-oxo-4H-pyrimido[1,2-c]quinazoline-3-carboxylate

N.M.R. δppm (CDCl₃): 1.43 (3H, t, J=7.5 Hz), 4.46 (2H, q, J=7.5 Hz),7.72 (1H, dd, J=2.0 and 9.0 Hz), 8.02 (1H, d, J=2 Hz), 8.80 (1H, d,J=9.0 Hz), 9.03 (1H, s), 9.66 (1H, s).

EXAMPLE 13

A mixture of 4-aminoquinazoline (7.27 g) and dimethylmethoxymethylenepropanedioate (9.6 g) in N,N-dimethylformamide (35 ml)was stirred for 2 hours at 150° C. The reaction mixture was cooled toambient temperature and poured into ice-water to give crystals, whichwere separated by filtration, washed with water and dried at ambienttemperature to give a mixture (13.3 g) of dimethyl[(4-quinazolinylamino)methylene]propanedioate and methyl4-oxo-4H-pyrimido[1,2-c]quinazoline-3-carboxylate.

(a) Dimethyl [(4-quinazolinylamino)methylene]propanedioate

N.M.R. δppm (CDCl₃): 3.87 (6H, s), 7.5-8.2 (4H, m), 9.07 (1H, s), 9.37(1H, d, J=12.0 Hz), 12.3 (1H, d, J=12.0 Hz).

(b) Methyl 4-oxo-4H-pyrimido[1,2-c]quinazoline-3-carboxylate

N.M.R. δppm (CDCl₃): 4.03 (3H, s), 7.6-8.12 (3H, m), 8.88 (1H, d, J=8.0Hz), 9.10 (1H, s), 9.73 (1H, s).

EXAMPLE 14

(a) A mixture of 4-amino-6,7-dimethylquinazoline (11.3 g) and diethylethoxymethylenepropanedioate (15.55 g) in N,N-dimethylformamide (45 ml)was stirred for 4 hours at 110° C. After the reaction mixture was cooledto ambient temperature, to the mixture was added water to give crystals,which were separated by filtration, washed with water and dried underreduced pressure to give crude crystals (18.5 g). The crude crustalswere dissolved in 1% methanol-chloroform solution (500 ml) andconcentrated under reduced pressure after insoluble materials wereremoved by filtration. The residue was recrystallized from chloroform togive crystalline ethyl9,10-dimethyl-4-oxo-4H-pyrimido[1,2-c]quinazoline-3-carboxylate (3.57g).

mp: 221°-223° C.

IR (Nujol) νmax: 1710, 1690, 1610, 810 cm⁻¹.

N.M.R. δppm (CDCl₃): 1.4 (3H, t, J=7.0 Hz), 2.5 (6H, s), 4.34 (2H,quartet, J=7.0 Hz), 7.8 (1H, s), 8.6 (1H, s), 9.7 (1H, s), 11.35 (1H,s).

(b) A mixture of ethyl9,10-dimethyl-4-oxo-4H-primido[1,2-c]quinazoline-3-carboxylate (4.46 g)and anhydrous dimethylsulfoxide (17 ml) was stirred at ambienttemperature. To the mixture was dropwise 1 N sodium-ethoxide-ethanolsolution (20 ml) and the reaction mixture was stirred for 3 hours atambient temperature. To the resultant mixture was added ammoniumchloride (2.45 g) and the mixture was stirred for 5 minutes. To themixture was added water and extracted twice with chloroform. Afterwashing three times with water and with aqueous solution saturated withsodium chloride, the combined chloroform layer was treated withactivated charcoal, dried over magnesium sulfate and concentrated underreduced pressure to give a residue, which was dissolved in a mixture ofchloroform and ethyl acetate. Insoluble materials were removed byfiltration. The filtrate was concentrated under reduced pressure andrecrystallized twice from ethyl acetate and from a mixture of chloroformand hexane to give diethyl[(6,7-dimethyl-4-quinazolinylamino)methylene]propanedioate (2.01 g).

mp: 146°-148° C.

IR (Nujol) νmax: 3160, 1730, 1690, 1655, 1625, 1615 cm⁻¹.

N.M.R. δppm (CDCl₃): 1.32 (3H, t, J=7.0 Hz), 1.4 (3H, t, J=7.0 Hz), 2.5(6H, s), 4.3 (2H, q, J=7.0 Hz), 4.43 (2H, q, J=7.0 Hz), 7.66 (1H, s),7.76 (1H, s), 8.9 (1H, s), 9.36 (1H, d, J=12.0 Hz), 11.56 (1H, d, J=12.0Hz).

EXAMPLE 15

A suspension of diethyl[(6-nitro-4-quinazolinylamino)methylene]propanedioate (2.8 g) inN,N-dimethylformamide (152 ml) was shaken with 10% palladium on carbon(0.93 g) in hydrogen atmosphere at ambient temperature for an hour.After the reaction was completed, the catalyst was removed by filtrationand washed with chloroform. The combined filtrate and washing wasconcentrated under reduced pressure to give a residue, to which wasadded toluene and concentrated under reduced pressure. This operationwas repeated to give crystalline diethyl[(6-amino-4-quinazolinylamino)methylene]propanedioate (2.50 g).

IR (Nujol) νmax: 3260, 1690, 1640, 1630, 1600 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 1.3 (3H, t, J=7.0 Hz), 1.35 (3H, t, J=7 Hz), 4.23(2H, quartet, J=7.0 Hz), 4.39 (2H, quartet, J=7.0 Hz), 7.2 (1H, d, J=2.0Hz), 7.4 (1H, dd, J=2 and 10 Hz), 7.83 (1H, d, J=10.0 Hz), 9.36 (1H, s),9.5-10 (3H, m), 12.3 (1H, d, J=14.0 Hz).

EXAMPLE 16

A mixture of diethyl[(6-amino-4-quinazolinylamino)methylene]propanedioate (2.5 g), pyridine(1.2 g) and dichloromethane (55 ml) was stirred under ice-cooling. Tothe reaction mixture was added dropwise isobutyryl chloride (1.06 g).The reaction mixture was stirred under ice-cooling for 30 minutes and atambient temperature for 20 minutes. After ice-water was added to thereaction mixture, the resultant mixture was stirred and extracted withchloroform. Insoluble materials were removed by filtration from theextracts. The extracts were washed three times with water and withaqueous solution saturated with sodium chloride, dried over magnesiumsulfate and concentrated under reduced pressure. The resultant residuewas purified by a column chromatography using silica gel (developingsolvent: chloroform) and crystallized from a mixture of chloroform andhexane to give crystalline diethyl[(6-isobutyramido-4-quinazolinylamino)methylene]propanedioate (1.28 g).Crystals (0.67 g) of the same compound were recovered from the motherliquor by substantially the same crystallization as mentioned above.

mp: 190°-193° C.

IR (Nujol) νmax: 3530, 1775, 1710, 1700, 1678, 1660, 1615 cm⁻¹.

N.M.R. δppm (CDCl₃): 1.2-1.5 (12H, m), 2.2-2.8 (1H, m), 4.25 (2H,quartet, J=6 Hz), 4.39 (2H, quartet, J=6 Hz), 7.4-8.2 (4H, m), 8.8 (1H,s), 9.15 (1H, d, J=12 Hz), 12.06 (1H, d, J=12 Hz).

EXAMPLE 17

The following compounds were prepared in substantially the same manneras that of Example 16.

(1) Diethyl [(6-acetamido-4-quinazolinylamino)methylene]propanedioate

mp: 178°-180° C. (recrystallized from a mixture of tetrahydrofuran andhexane).

IR (Nujol) νmax: 3380, 1695, 1660, 1630, 1610 cm⁻¹.

N.M.R. δppm (CDCl₃): 1.32 (3H, t, J=6 Hz), 1.36 (3H, t, J=6 Hz), 2.08(3H, s), 4.3 (4H, quartet, J=6 Hz), 7.7-8.1 (2H, m), 8.44 (1H, s), 8.83(1H, s), 9.28 (1H, s), 9.28 (1H, d, J=12 Hz), 11.98 (1H, d, J=12 Hz).

(2) Diethyl [(6-propionamido-4-quinazolinylamino)methylene]propanedioate

mp: 190°-193° C. (recrystallized from a mixture of ethyl acetate andhexane).

IR (Nujol) νmax: 3340, 1736, 1670, 1660, 1635, 1572 cm⁻¹.

N.M.R. δppm (CDCl₃): 1.2-1.6 (9H, m), 2.50 (2H, quartet, J=7.0 Hz), 4.34(2H, quartet, J=7.0 Hz), 4.40 (2H, quartet, J=7.0 Hz), 8.0 (2H, m), 8.40(1H, broad s), 8.56 (1H, s), 8.90 (1H, s), 9.36 (1H, d, J=12 Hz), 12.1(1H, d, J=12 Hz).

(3) Diethyl [(6-butyramido-4-quinazolinylamino)methylene]propanedioate

mp: 187°-190° C. (recrystallized from methanol)

IR (Nujol) νmax: 3380, 1748, 1680, 1625, 1580, 1554 cm⁻¹.

N.M.R. δppm (CDCl₃): 0.98 (3H, t, J=7.0 Hz), 1.27 (3H, t, J=6.8 Hz),1.33 (3H, t, J=6.8 Hz), 1.80 (2H, m), 2.43 (2H, t, J=7 Hz), 4.33 (4H,m), 8.0 (2H, m), 8.43 (1H, broad s), 8.90 (2H, s), 9.40 (1H, d, J=12Hz), 12.1 (1H, d, J=12 Hz).

(4) Diethyl [(6-hexanamido-4-quinazolinylamino)methylene]propanedioate

mp: 157°-162° C. (recrystallized from chloroform, ethylacetate andhexane).

IR (Nujol) νmax: 1686, 1640, 1620, 1600, 1550 cm⁻¹.

N.M.R. δppm (CDCl₃): 0.6-1.2 (3H, m), 1.2-2.2 (12H, m), 2.80 (2H, broadt, J=7.0 Hz), 4.36 (4H, m), 7.83 (1H, d, J=9.0 Hz), 8.1-8.5 (2H, m),8.76 (1H, s), 9.16 (1H, d, J=12 Hz), 10.2 (1H, s), 12.3 (1H, d, J=12Hz).

(5) Diethyl [(6-ethoxalamido-4-quinazolinylamino)methylene]propanedioate

mp: 191°-192° C. (recrystallized from chloroform, ethylacetate andhexane).

IR (Nujol) νmax: 3300, 1720, 1685, 1650, 1630, 1610 cm⁻¹.

N.M.R. δppm (CDCl₃): 1.27-1.66 (9H, m), 4.17-4.66 (6H, m), 7.9-8.27 (2H,m), 8.50 (1H, broad s), 8.93 (1H, s), 9.33 (1H, d, J=12.0 Hz), 9.43 (1H,s), 12.23 (1H, d, J=12.0 Hz).

(6) Diethyl[(6-cyclohexanamido-4-quinazolinylamino)methylene]propanedioate

mp: 202°-208° C. (recrystallized from a mixture of chloroform andmethanol).

IR (Nujol) νmax: 3340, 1728, 1660, 1634, 1615, 1570 cm⁻¹.

N.M.R. δppm (CDCl₃): 1.37 (6H, t, J=7.0 Hz), 1.0-2.6 (11H, m), 4.37 (4H,m), 7.8-8.2 (3H, m), 8.33 (1H, broad s), 8.90 (1H, s), 9.37 (1H, d,J=12.0 Hz), 12.1 (1H, d, J=12.0 Hz).

(7) Diethyl [(6-benzamido-4-quinazolinylamino)methylene]propanedioate

mp: 164°-165° C. (recrystallized from a mixture of chloroform andhexane).

IR (Nujol) νmax: 3400, 1715, 1710, 1660, 1640, 1610 cm⁻¹.

N.M.R. δppm (CDCl₃): 1.33 (6H, t, J=8.0 Hz), 4.30 (2H, quartet, J=8.0Hz), 4.33 (2H, quartet, J=8.0 Hz), 7.4-8.3 (7H, m), 8.46 (1H, s), 8.7(1H, s), 8.90 (1H, s), 9.33 (1H, d, J=12 Hz), 12.1 (1H, d, J=12 Hz).

(8) Diethyl[(6-phenylacetamido-4-quinazolinylamino)methylene]propanedioate

mp: 113°-117° C. (recrystallized from a mixture of ether and hexane).

IR (Nujol) νmax: 3600, 1748, 1710, 1690, 1660, 1632, 1620 cm⁻¹.

N.M.R. δppm (CDCl₃): 1.33 (3H, t, J=7.0 Hz), 1.37 (3H, t, J=7.0 Hz),3.80 (2H, s), 4.33 (4H, m), 7.33 (5H, s), 7.83 (2H, broad s), 8.43 (2H,broad s), 8.83 (1H, s), 9.33 (1H, d, J=12 Hz), 12.0 (1H, d, J=12 Hz).

(9) Diethyl [(6-pivalamido-4-quinazolinylamino)methylene]propanedioate

mp: 141°-142° C. (recrystallized from a mixture of ether and ethylacetate.

IR (Nujol) νmax: 3380, 1720, 1672, 1652, 1628, 1610 cm⁻¹.

N.M.R. δppm (CDCl₃): 1.2-1.7 (15H, m), 4.2-4.7 (4H, m), 7.7-8.16 (3H,m), 8.33 (1H, s), 8.83 (1H, s), 9.33 (1H, d, J=12 Hz), 12.0 (1H, d, J=12Hz).

EXAMPLE 18

A mixture of diethyl[(6-amino-4-quinazolinylamino)methylene]propanedioate (3.03 g), pyridine(3.63 g) and dichloromethane (93 ml) was ice-cooled. To the mixture wasadded acetic anhydride (1.88 g). The reaction mixture was stirred for 30minutes under ice-cooling and then for 2 hours and 15 minutes at ambienttemperature. Ice water was added to the mixture. The resultant mixturewas extracted with chloroform. The organic layer was washed three timeswith water and with aqueous solution saturated with sodium chloride,dried over anhydrous magnesium sulfate and concentrated under reducedpressure to give a residue, which was purified by a columnchromatography on silica gel (developing solvent: chloroform) andrecrystallized from chloroform, ethyl acetate and hexane to givecrystalline diethyl[(6-acetamido-4-quinazolinylamino)methylene]propanedioate (2.2 g).

N.M.R. δppm (CDCl₃): 1.32 (3H, t, J=6 Hz), 1.36 (3H, t, J=6 Hz), 2.08(3H, s), 4.3 (4H, quartet, J=6 Hz), 7.7-8.1 (2H, m), 8.44 (1H, s), 8.83(1H, s), 9.28 (1H, s), 9.28 (1H, d, J=12 Hz), 11.98 (1H, d, J=12 Hz).

EXAMPLE 19

A suspension of diethyl[(6-nitro-4-quinazolinylamino)methylene]propanedioate (0.7 g) inN,N-dimethylformamide (56 ml) was shaken with 10% palladium on carbon(60 mg) in hydrogen atmosphere at ambient temperature until hydrogen gas(160 ml) was absorbed. The catalyst was removed by filtration and washedwith a small volume of chloroform. To the combined filtrate and washingswas added a mixture of acetic anhydride (15 ml) and pyridine (15 ml) andthe reaction mixture was allowed at ambient temperature for 1 day. Thereaction mixture was concentrated under reduced pressure to give aresidue, to which was added toluene and the mixture was concentratedunder reduced pressure. This operation was repeated twice to removeN,N-dimethylformamide and acetic anhydride. The resultant residue wassubjected to fractionation on silica gel column (developing solvent:ethyl acetate and chloroform) to give crude crystals of diethyl[(6-N,N-diacetylamino-4-quinazolinylamino)methylene]propanedioate (0.24g). The crude crystals were recrystallized from a mixture of ethylacetate and hexane to give purified crystals of the same compound.

mp: 148°-151° C.

IR (Nujol) νmax: 1800, 1700, 1645, 1608 cm⁻¹.

N.M.R. δppm (CDCl₃): 1.24-1.52 (6H, m), 2.24 (3H, s), 2.40 (3H, s),4.22-4.55 (4H, m), 7.92 (1H, d, J=2.0 Hz), 7.98 (1H, d, J=9.0 Hz), 8.16(1H, dd, J=2.0 and 9.0 Hz), 8.92 (1H, s), 9.3 (1H, d, J=12.0 Hz), 12.24(1H, broad d, J=12.0 Hz).

EXAMPLE 20

A suspension of diethyl[(6-nitro-4-quinazolinylamino)methylene]propanedioate (10.8 g) inN,N-dimethylformamide (380 ml) was shaken with 10% palladium on carbon(3.6 g) in hydrogen atmosphere at ambient temperature until hydrogen gas(2030 ml) was absorbed. The catalyst was removed by filtration andwashed with a small volume of N,N-dimethylformamide. To the combinedfiltrate and washings was added pyridine (17 ml) and the mixture wascooled over an ice-bath. To the solution was added dropwise pivalicchloride (6.33 g) for 20 minutes and then the reaction mixture wasstirred for 2 hours and 40 minutes at ambient temperature. To theresultant mixture was added ice-water under stirring and then themixture was concentrated under reduced pressure. To the residue wasadded chloroform and then the mixture was washed with an aqueoussolution saturated with sodium bicarbonate and with water. Insolublematerials were removed by filtration from the chloroform layer. Thefiltrate was washed with aqueous solution saturated with sodiumchloride, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The resultant oil was subjected to a chromatographyusing silica gel (developing solvent: dichloromethane) to give the firstFraction A and the second Fraction B. The Fraction A was concentratedunder reduced pressure to give crystalline diethyl[(6-pivalamido-4-quinazolinylamino)methylene]propanedioate (4.6 g).Further, Fraction B was concentrated under reduced pressure to give asolid (3.6 g), which was suspended in methanol. Insoluble materials wereseparated by filtration and recrystallized from ethyl acetate to givecrystalline diethyl[(6-formamido-4-quinazolinylamino)methylene]propanedioate (0.58 g).

mp: 182°-185° C.

EXAMPLE 21

To diethyl [(4-quinazolinylamino)methylene]propanedioate (16.0 g) wasadded diphenylether (70 ml) which had been heated at 250° C. in advance.The reaction mixture was stirred at 250°-260° C. for 20 minutes andcooled to ambient temperature. To the resultant mixture was addedhexane. The mixture was stirred to give crystals, which was washed withhexane and dried. The crude crystals were dissolved in ethyl acetateunder heating. After insoluble materials were removed by filtration, thefiltrate was concentrated under reduced pressure to a volume of 200 ml.To the concentrate was added hexane and the mixture was allowed to standat ambient temperature to precipitate crystals, which were separated byfiltration, washed with a mixture of ethyl acetate and hexane and driedto give crystalline ethyl4-oxo-4H-pyrimido[1,2-c]quinazoline-3-carboxylate (12.4 g).

mp: 171°-172° C.

IR (Nujol) νmax: 1725, 1702, 1620 cm⁻¹.

N.M.R. δppm (CDCl₃): 1.43 (3H, t, J=7.0 Hz), 4.40 (2H, quartet, J=7.0Hz), 7.6-8.2 (3H, m), 8.84 (1H, broad d, J=7.0 Hz), 9.03 (1H, s), 9.66(1H, s).

EXAMPLE 22

The following compounds were prepared in substantially the same manneras that of Example 21.

(1) Methyl 4-oxo-4H-pyrimido[1,2-c]quinazoline-3-carboxylate

mp: 203°-205° C. (recrystallized from chloroform).

N.M.R. δppm (CDCl₃): 4.03 (3H, s), 7.6-8.12 (3H, m), 8.88 (1H, d, J=8.0Hz), 9.10 (1H, s), 9.73 (1H, s).

(2) Ethyl 4-oxo-10-chloro-4H-pyrimido[1,2-c]quinazoline-3-carboxylate

mp: 161°-163° C. (recrystallized from a mixture of chloroform andhexane).

IR (Nujol) νmax: 1752, 1700, 1621, 1584 cm⁻¹.

N.M.R. δppm (CDCl₃): 1.43 (3H, t, J=7.0 Hz), 4.40 (2H, quartet, J=7.0Hz), 7.88 (2H, broad s), 8.70 (1H, m), 8.93 (1H, s), 9.54 (1H, s).

(3) Ethyl 4-oxo-9-chloro-4H-pyrimido[1,2-c]quinazoline-3-carboxylate

mp: 192.5°-193.5° C. (recrystallized from a mixture of diphenyl etherand hexane).

IR (Nujol) νmax: 1755, 1710, 1610, 1603, 1580 cm⁻¹.

N.M.R. δppm (CDCl₃): 1.43 (3H, t, J=7.5 Hz), 4.46 (2H, quartet, J=7.5Hz), 7.72 (1H, dd, J=2.0 and 9.0 Hz), 8.02 (1H, d, J=2 Hz), 8.80 (1H, d,J=9.0 Hz), 9.03 (1H, s), 9.66 (1H, s).

(4) Ethyl 4-oxo-10-methyl-4H-pyrimido[1,2-c]quinazoline-3-carboxylate

mp: 182°-183° C. (recrystallized from a mixture of chloroform, ethylacetate and hexane).

IR (Nujol) νmax: 1752, 1690, 1614 cm⁻¹.

N.M.R. δppm (CDCl₃): 1.42 (3H, t, J=7.8 Hz), 2.56 (3H, s), 4.40 (2H,quartet, J=7.8 Hz), 7.76 (2H, m), 8.52 (1H, broad s), 8.92 (1H, s), 9.50(1H, s).

(5) Ethyl 4-oxo-10-nitro-4H-pyrimido[1,2-c]quinazoline-3-carboxylate

mp: 171°-174° C. (recrystallized from a mixture of chloroform andhexane).

IR (Nujol) νmax: 1720, 1700, 1625, 1585 cm⁻¹.

N.M.R. δppm (CDCl₃): 1.43 (3H, t, J=6.0 Hz), 4.36 (2H, quartet, J=6.0Hz), 8.16 (1H, d, J=9.0 Hz), 8.73 (1H, dd, J=3.0 and 9.0 Hz), 9.03 (1H,s), 9.66 (1H, d, J=3.0 Hz), 9.73 (1H, s).

(6) Ethyl 4-oxo-10-phenoxy-4H-pyrimido[1,2-c]quinazoline-3-carboxylate

mp: 210°-213° C. (recrystallized from a mixture of chloroform, ethylacetate and hexane).

IR (Nujol) νmax: 1750, 1680, 1618, 1593 cm⁻¹.

N.M.R. δppm (CDCl₃): 1.43 (3H, t, J=7.0 Hz), 4.43 (2H, d, J=7.0 Hz),7.0-8.4 (7H, m), 8.0 (1H, d, J=8.0 Hz), 9.0 (1H, s), 9.63 (1H, s).

(7) Ethyl4-oxo-10-(dimethylamino)-4H-pyrimido[1,2-c]quinazoline-3-carboxylate

mp: 240°-242° C. (recrystallized from tetrahydrofuran).

IR (Nujol) νmax: 1745, 1685, 1612, 1595 cm⁻¹.

N.M.R. δppm (CDCl₃): 1.44 (3H, t, J=7.5 Hz), 3.16 (6H, s), 4.44 (2H,quartet, J=7.5 Hz), 7.3-7.5 (2H, m), 7.80 (1H, m), 8.98 (1H, s), 9.44(1H, s).

(8) Ethyl 4-oxo-10-ethylthio-4H-pyrimido[1,2-c]quinazoline-3-carboxylate

mp: 168°-170° C. (recrystallized from a mixture of chloroform andhexane).

IR (Nujol) νmax: 1750, 1695, 1610, 1495 cm⁻¹

N.M.R. δppm (CDCl₃): 1.45 (6H, t, J=8.0 Hz), 3.16 (2H, quartet, J=8.0Hz), 4.47 (2H, quartet, J=8.0 Hz), 7.8-8.0 (2H, m), 8.6 (1H, m), 9.03(1H, s), 9.60 (1H, s).

(9) Ethyl 4-oxo-9-methoxy-4H-pyrimido[1,2-c]quinazoline-3-carboxylate

mp: 202°-206° C. (recrystallized from a mixture of chloroform andhexane).

IR (Nujol) νmax: 1740, 1680, 1615, 1585 cm⁻¹.

N.M.R. δppm (CDCl₃): 1.43 (3H, t, J=7.0 Hz), 4.00 (3H, s), 4.43 (2H,quartet, J=7.0 Hz), 7.40 (2H, m), 8.77 (1H, d, J=10.0 Hz), 9.00 (1H, s),9.67 (1H, s).

(10) Ethyl4-oxo-10-acetamido-4H-pyrimido[1,2-c]quinazoline-3-carboxylate

mp: 294°-295° C. (recrystallized from N,N-dimethylformamide).

IR (Nujol) νmax: 3360, 1740, 1720, 1675, 1615 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 1.3 (3H, t, J=6.0 Hz), 2.1 (3H, s), 4.30 (2H,quartet, J=6.0 Hz), 7.83 (1H, d, J=9.0 Hz), 8.1 (1H, dd, J=2.0 and 9.0Hz), 8.87 (1H, s), 9.03 (1H, d, J=2.0 Hz), 9.36 (1H, s), 10.46 (1H, s).

(11) Ethy 4-oxo-9-acetamido-4H-pyrimido[1,2-c]quinazoline-3-carboxylate

mp: 281°-285° C. (recrystallized from a mixture of N,N-dimethylformamideand water).

IR (Nujol) νmax: 3560, 3400, 1742, 1616, 1588 cm⁻¹.

(12) Ethyl4-oxo-10-propionamido-4H-pyrimido[1,2-c]quinazoline-3-carboxylate

mp: 274°-276° C. (recrystallized from a mixture of chloroform andmethanol).

IR (Nujol) νmax: 3360, 1740, 1720, 1670, 1618 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 1.13 (3H, t, J=7.0 Hz), 1.30 (3H, t, J=7.0 Hz),2.43 (2H, quartet, J=7.0 Hz), 4.30 (2H, quartet, J=7.0 Hz), 7.90 (1H, d,J=10.0 Hz), 8.16 (1H, dd, J=2.0 and 10.0 Hz), 8.90 (1H, s), 9.10 (1H, d,J=2.0 Hz), 9.40 (1H, s), 10.43 (1H, s).

(13) Ethyl4-oxo-10-butyramido-4H-pyrimido[1,2-c]quinazoline-3-carboxylate

mp: 278°-282° C. (recrystallized from a mixture of chloroform andmethanol).

IR (Nujol) νmax: 3410, 1745, 1712, 1680, 1615 cm⁻¹.

N.M.R. δppm (CDCl₃): 1.03 (3H, t, J=7.0 Hz), 1.43 (3H, t, J=7.0 Hz),1.76 (2H, m), 2.46 (2H, t, J=7.0 Hz), 4.46 (2H, quartet, J=7.0 Hz), 8.0(1H, d, J=9.0 Hz), 8.43 (1H, dd, J=2.0 and 9.0 Hz), 8.97 (1H, d, J=2.0Hz), 9.05 (1H, s), 9.63 (1H, s).

(14) Ethyl4-oxo-10-isobutyramido-4H-pyrimido[1,2-c]quinazoline-3-carboxylate

mp: 245°-247° C. (recrystallized from a mixture of chloroform andhexane).

IR (Nujol) νmax: 3400, 1730, 1710, 1690, 1625, 1410 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 1.2-1.8 (9H, m), 2.3-2.9 (1H, m), 4.46 (2H,quartet, J=7.0 Hz), 7.8-8.1 (2H, m), 8.43 (1H, dd, J=2 and 10 Hz), 8.92(1H, d, J=2 Hz), 9.05 (1H, s), 9.63 (1H, s).

(15) Ethyl4-oxo-10-hexanamido-4H-pyrimido[1,2-c]quinazoline-3-carboxylate

mp: 231°-234° C. (recrystallized from a mixture of chloroform andmethanol).

IR (Nujol) νmax: 3400, 3100, 1745, 1720, 1680, 1610 cm⁻¹.

N.M.R. δppm (DMSO₄ -d₆): 0.6-2.0 (10H, m), 2.1-2.6 (4H, m), 4.30 (2H,quartet), J=7.0 Hz), 7.9 (1H, d, J=9.0 Hz), 8.16 (1H, dd, J=2.0 and 9.0Hz), 8.90 (1H, s), 9.13 (1H, d, J=2.0 Hz), 9.40 (1H, s), 10.55 (1H, s).

(16) Ethyl4-oxo-10-ethoxalamido-4H-pyrimido[1,2-c]quinazoline-3-carboxylate

mp: 263°-264° C. (recrystallized from a mixture of chloroform andmethanol).

IR (Nujol) νmax: 3400, 1745, 1725, 1610 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 1.26 (3H, t, J=6 Hz), 1.30 (3H, t, J=6 Hz), 4.3(2H, quartet, J=6 Hz), 4.36 (2H, quartet, J=6 Hz), 7.96 (1H, d, J=9.0Hz), 8.33 (1H, dd, J=2 and 9 Hz), 8.9 (1H, s), 9.27 (1H, d, J=2 Hz),9.43 (1H, s), 11.4 (1H, s).

(17) Ethyl4-oxo-10-cyclohexanecarboxamido-4H-pyrimido-[1,2-c]quinazoline-3-carboxylate

mp: 262°-266° C. (recrystallized from a mixture of chloroform andhexane).

IR (Nujol) νmax: 3400, 3100, 1730, 1692, 1672, 1612 cm⁻¹.

N.M.R. δppm (CDCl₃): 1.40 (3H, t, J=7.0 Hz), 1.0-2.6 (11H, m), 4.46 (2H,quartet, J=7.0 Hz), 7.90 (1H, s), 8.0 (1H, d, J=9.0 Hz), 8.43 (1H, dd,J=3.0 and 9.0 Hz), 8.93 (1H, d, J=3.0 Hz), 9.1 (1H, s), 9.66 (1H, s).

(18) Ethyl4-oxo-10-benzamido-4H-pyrimido[1,2-c]quinazoline-3-carboxylate

mp: 237°-239° C. (recrystallized from a mixture of chloroform andmethanol).

IR (Nujol) νmax: 3400, 1730, 1680, 1620 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 1.40 (3H, t, J=7.0 Hz), 4.40 (2H, quartet, J=7.0Hz), 7.5-8.3 (6H, m), 8.55 (1H, dd, J=2.0 and 10.0 Hz), 9.0 (1H, s),9.40 (1H, d, J=2.0 Hz), 9.53 (1H, s), 10.86 (1H, s).

(19) Ethyl4-oxo-10-phenylacetamido-4H-pyrimido[1,2-c]quinazoline-3-carboxylate

mp: 230°-235° C. (recrystallized from a mixture of methanol andchloroform).

IR (Nujol) νmax: 3370, 1735, 1720, 1670, 1618 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 1.3 (3H, t, J=7.0 Hz), 3.75 (2H, s), 4.33 (2H,quartet, J=7.0 Hz), 7.33 (5H, s), 7.8-8.3 (2H, m), 8.90 (1H, s), 9.12(1H, d, J=2 Hz), 9.40 (1H, s), 10.76 (1H, s).

(20) Ethyl 4-oxo-10-ethyl-pyrimido[1,2-c]quinazoline-3-carboxylate

mp: 168°-170° C. (recrystallized from a mixture of ethyl acetate andhexane).

IR (Nujol) νmax: 1720, 1700, 1620, 1500 cm⁻¹.

N.M.R. δppm (CDCl₃): 1.4 (3H, t, J=8.0 Hz), 1.46 (3H, t, J=8.0 Hz), 2.95(2H, quartet, J=8.0 Hz), 4.46 (2H, quartet, J=8.0 Hz), 7.9-8.1 (2H, m),8.7 (1H, s), 9.06 (1H, s), 9.66 (1H, s).

(21) Ethyl 4-oxo-10-butyl-pyrimido[1,2-c]quinazoline-3-carboxylate

mp: 151°-154° C. (recrystallized from a mixture of ethyl acetate andhexane).

IR (Nujol) νmax: 1720, 1690, 1610, 1490, 800 cm⁻¹.

N.M.R. δppm (CCl₄): 0.8-2.1 (10H, m), 2.9 (2H, t, J=8.0 Hz), 4.43 (2H,quartet, J=7.0 Hz), 7.7-8.0 (2H, m), 8.63 (1H, s), 8.9 (1H, s), 9.53(1H, s).

(22) Ethyl 4-oxo-8-methyl-4H-pyrimido[1,2-c]quinazoline-3-carboxylate

mp: 166°-172° C. (recrystallized from a mixture of chloroform, ethylacetate and hexane).

IR (Nujol) νmax: 1750, 1692, 1622, 1600 cm⁻¹.

N.M.R. δppm (CDCl₃): 1.46 (3H, t, J=7.0 Hz), 2.73 (3H, s), 4.46 (2H,quartet, J=7.0 Hz), 7.4-7.9 (2H, m), 8.60 (1H, broad d, J=8.0 Hz), 8.93(1H, s), 9.56 (1H, s).

(23) Ethyl 4-oxo-10-propyl-4H-pyrimido[1,2-c]quinazoline-3-carboxylate

mp: 161°-163° C. (recrystallized from benzene).

IR (Nujol) νmax: 1700, 1620, 1610, 1500, 1150 cm⁻¹.

N.M.R. δppm (CDCl₃): 1.0 (3H, t, J=7.0 Hz), 1.3-2.2 (5H, m), 2.9 (2H, t,J=7.0 Hz), 4.43 (2H, quartet, J=7.0 Hz), 7.8-8.1 (2H, m), 8.63 (1H, s),9.0 (1H, s), 9.6 (1H, s).

(24) Ethyl 4-oxo-9-methyl-4H-pyrimido[1,2-c]quinazoline-3-carboxylate

mp: 186°-188° C. (recrystallized from tetrahydrofuran).

IR (Nujol) νmax: 1705, 1680, 1490, 1300, 800 cm⁻¹.

N.M.R. δppm (CDCl₃): 1.4 (3H, t, J=8.0 Hz), 2.6 (3H, s), 4.33 (2H,quartet, J=8.0 Hz), 7.56 (1H, d, J=8.0 Hz), 7.76 (1H, s), 8.7 (1H, d,J=8.0 Hz), 9.0 (1H, s), 9.63 (1H, s).

(25) Ethyl4-oxo-10-(4-methylpiperazinyl)-4H-pyrimido-[1,2-c]quinazoline-3-carboxylat

mp: 203°-206° C. (recrystallized from a mixture of ethanol andchloroform).

IR (Nujol) νmax: 1740, 1680, 1608 cm⁻¹.

N.M.R. δppm (CDCl₃): 1.43 (3H, t, J=7.0 Hz), 2.36 (3H, s), 2.60 (4H, m),3.46 (4H, m), 4.43 (2H, quartet, J=7.0 Hz), 7.50 (1H, dd, J=3.0 and 8.5Hz), 7.80 (1H, d, J=8.5 Hz), 8.03 (1H, d, J=3.0 Hz), 8.96 (1H, s), 9.46(1H, s).

(26) Ethyl4-oxo-9,10-dimethoxy-4H-pyrimido[1,2-c]quinazoline-3-carboxylate

mp: 262°-264° C. (recrystallized from chloroform).

IR (Nujol) νmax: 1705, 1675, 1595 cm⁻¹.

N.M.R. δppm (CDCl₃): 1.43 (3H, t, J=7.0 Hz), 4.13 (6H, s), 4.46 (2H,quartet, J=7.0 Hz), 7.40 (1H, s), 8.16 (1H, s), 9.05 (1H, s), 9.67 (1H,s).

(27) Ethyl4-oxo-10-pivalamido-4H-pyrimido[1,2-c]quinazoline-3-carboxylate

mp: 247°-250° C. (recrystallized from a mixture of chloroform andmethanol).

IR (Nujol) νmax: 3370, 1712, 1672, 1610 cm⁻¹.

N.M.R. δppm (CDCl₃): 1.45 (3H, t, J=7.0 Hz), 1.37 (9H, s), 4.46 (2H,quartet, J=7.0 Hz), 7.96 (1H, d, J=9.5 Hz), 8.41 (1H, dd, J=3 and 9.5Hz), 9.13 (2H, broad s), 9.63 (1H, s), 12.1 (1H, s).

(28) Ethyl 4-oxo-6-hydroxy-4H-pyrimido[1,2-c]quinazoline-3-carboxylate

mp: >270° C. (recrystallized from a mixture of chloroform and methanol).

IR (Nujol) νmax: 1770, 1742, 1705, 1638, 1615, 1602 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 1.32 (3H, t, J=6.0 Hz), 4.30 (2H, quartet, J=6.0Hz), 7.2-7.6 (2H, m), 7.74 (1H, t, J=8.0 Hz), 8.26 (1H, d, J=8.0 Hz),8.92 (1H, s), 12.5 (1H, broad s).

(29) Ethyl 4-oxo-6-methyl-4H-pyrimido[1,2-c]quinazoline-3-carboxylate

mp: 167°-168° C. (recrystallized from benzene)

IR (Nujol) νmax: 1735, 1700, 1615, 1590 cm⁻¹.

N.M.R. δppm (CDCl₃): 1.43 (3H, t, J=7.0 Hz), 3.20 (3H, s), 4.47 (2H,quartet J=7.0 Hz), 7.6-8.0 (3H, m), 8.73-8.93 (1H, m), 8.93 (1H, s).

(30) Ethyl4-oxo-6-hydroxy-10-ethyl-4H-pyrimido[1,2-c]quinazolin-3-carboxylate

mp: 315°-318° C. (recrystallized from a mixture of chloroform andmethanol).

IR (Nujol) νmax: 1748, 1630, 1595 cm⁻¹.

EXAMPLE 23

A mixture of diethyl[(2-allyloxy-4-quinazolinylamino)methylene]propanedioate (6.0 g) indiphenyl ether (14 ml) was stirred for 15 minutes at 260° C. and thencooling to ambient temperature. Hexane was added to the resultantmixture to give precipitates, which separated by filtration and washedwith hexane to give crude crystals. The crude crystals were subjected toa column chromatography using silica gel (developing solvent:chloroform) to give the first Fraction A and the second Fraction B.

The fraction A was concentrated under reduced pressure to give crystals,which were recrystallized from a mixture of chloroform, ethyl acetateand hexane to give crystalline ethyl4-oxo-6-allyloxy-4H-pyrimido-[1,2-c]quinazoline-3-carboxylate (1.8 g).

mp: 191°-195° C.

IR (Nujol) νmax: 1775, 1725, 1690, 1608 cm⁻¹.

N.M.R. δppm (CDCl₃): 1.40 (3H, t, J=7.0 Hz), 4.43 (2H, quartet, J=7.0Hz), 4.90 (2H, m), 5.40 (2H, m), 6.0 (1H, m), 7.30 (2H, m), 7.80 (1H, t,J=7.0 Hz), 8.56 (1H, d, J=7.0 Hz), 8.66 (1H, s).

On the other hand, the Fraction B was concentrated under reducedpressure to give crystals, which were recrystallized from a mixture ofethyl acetate and hexane to give crystalline ethyl4,6-dioxo-7-allyl-4H-6,7-dihydropyrimido[1,2-c]quinazoline-3-carboxylate(1.5 g).

mp: 163°-166° C.

IR (Nujol) νmax: 1740, 1710, 1682, 1645, 1615, 1600 cm⁻¹.

N.M.R. δppm (CDCl₃): 1.40 (3H, t, J=7.0 Hz), 4.40 (2H, quartet, J=7.0Hz), 4.88 (2H, m), 5.24 (2H, m), 6.92 (1H, m), 7.34 (2H, m), 7.74 (1H,t, J=8.0 Hz), 8.60 (1H, d, J=7.0 Hz), 9.14 (1H, s).

EXAMPLE 24

A mixture of diethyl[(2-methoxy-4-quinazolinylamino)methylene]propanedioate (8.0 g) indiphenylether (30 ml) was stirred for 32 minutes at 260° C. The reactionmixture was allowed to stand overnight at ambient temperature to givecrystals, which were separated by filtration and washed with hexane togive crude crystals (A). Further, a large volume of hexane was added tothe filtrate and the mixture was allowed to stand overnight at ambienttemperature to give crystals, which were recrystallized from a mixtureof ethyl acetate and hexane to give crude crystals (B) and mother liquor(A). The crude crystals (A) and (B) were combined and subjected to acolumn chromatography using silica gel (developing solvent: a mixture ofethyl acetate and chloroform=1:9). One of the fractions was concentratedunder reduced pressure to give crystals, which were recrystallized froma mixture of chloroform and hexane to give crystalline ethyl4,6-dioxo-7-methyl-4H,6H-6,7-dihydropyrimido[1,2-c]quinazoline-3-carboxylate(0.7 g).

mp: 265°-271° C.

IR (Nujol) νmax: 1732, 1642, 1610 cm⁻¹.

N.M.R. δppm (CDCl₃): 1.40 (3H, t, J=7.8 Hz), 3.80 (3H, s), 4.45 (2H,quartet, J=7.8 Hz), 7.30-8.00 (3H, m), 8.73 (1H, d, J=8.0 Hz), 9.22 (1H,s).

Further, mother liquor (A) was concentrated under reduced pressure andsubjected to a column chromatography using silica gel (developingsolvent: chloroform). The eluate was concentrated under reduced pressureto give crystals, which were recrystallized from a mixture of chloroformand hexane to give crystalline ethyl4-oxo-6-methoxy-4H-pyrimido[1,2-c]quinazoline-3-carboxylate (0.45 g).

mp: 180°-183° C.

IR (Nujol) νmax: 1765, 1708, 1625, 1610, 1590 cm⁻¹.

N.M.R. δppm (CDCl₃): 1.46 (3H, t, J=7.0 Hz), 4.33 (3H, s), 4.46 (2H,quartet, J=7.0 Hz), 7.3-8.0 (3H, m), 8.70 (1H, d, J=7.0 Hz), 8.86 (1H,s).

EXAMPLE 25

A mixture of tetraethyl2,2'-[2,4-quinazolinediylbis(iminomethylidyne)]bispropanedioate (2.2 g)in diphenylether (11 ml) was stirred for 35 minutes at 260° C. and thencooled to ambient temperature. To the reaction mixture was added hexaneto give crystals, which were separated by filtration and dried to givecrude crystals (1.3 g), which were recrystallized from ethanol to givediethyl4,9-dioxo-4H,9H-pyrimido[1,2-c]pyrimido[1,2-a]quinazoline-3,8-dicarboxylate(0.9 g).

mp: 193°-195° C.

IR (Nujol) νmax: 1760, 1720, 1680, 1640, 1600 cm⁻¹.

N.M.R. δppm (CDCl₃): 1.43 (6H, t, J=8.0 Hz), 4.40 (4H, quartet, J=8.0Hz), 7.5-8.0 (2H, m), 8.67 (1H, s), 8.67-9.16 (2H, m), 9.73 (1H, s).

EXAMPLE 26

A mixture of2,2-dimethyl-5-[(4-quinazolinyl)amino]methylene-1,3-dioxane-4,6-dione,(3.5 g) in diphenylether (15 ml) was stirred for 10 minutes at 250°-260°C. and then cooled to ambient temperature. To the reaction mixture wasadded hexane and allowed to to stand at ambient temperature to givecrystals, which were separated by filtration and washed with hexane togive crude crystals (3 g). The crude crystals were subjected to a columnchromatography using silica gel (developing solvent: a mixture of ethylacetate and hexane (3:7)). The eluate was concentrated under reducedpressure to give crystals, which were recrystallized from chloroform andhexane to give 4H-pyrimido[1,2-c]quinazoline-4-one (1.6 g).

mp: 181°-183° C.

IR (Nujol) νmax: 1700, 1625, 1610, 1582 cm⁻¹.

N.M.R. δppm (CDCl₃): 6.57 (1H, d, J=7.0 Hz), 7.86 (3H, m), 8.27 (1H, d,J=7.0 Hz), 8.76 (1H, broad d, J=8.0 Hz), 9.53 (1H, s).

EXAMPLE 27

A mixture of methyl 4-oxo-4H-pyrimido[1,2-c]quinazoline-3-carboxylate(6.3 g) and lithium iodide (15.8 g) in N,N-dimethylformamide (100 ml)was stirred for 2 hours and a half at 150° C. and then cooled to ambienttemperature. To the reaction mixture was added water separated byfiltration, washed with water (600 ml) and dried to give crystalline4-oxo-4H-pyrimido[1,2-c]quinazoline-3-carboxylic acid (0.9 g).

mp: >270° C.

IR (Nujol) νmax: 1720, 1620 cm⁻¹.

N.M.R. δppm (CF₃ COOH): 8.10-8.66 (3H, m), 8.9-9.2 (1H, m), 9.53 (1H,s), 10.16 (1H, s).

EXAMPLE 28

A mixture of 4-amino-6-(3,3-dimethylbutyramido)quinazoline (8.5 g),dimethyl methoxymethylenepropanedioate (12.75 g) andN,N-dimethylformamide (34 g) was stirred for an hour at 100° C. Aftercooling to ambient temperature, to the resultant mixture was added waterto give precipitates, which were separated by filtration, washed withwater and dried to give crystalline dimethyl[{6-(3,3-dimethylbutyramido)-4-quinazolinylamino}methylene]propanedioate(10.9 g).

mp: 196°-198° C.

IR (Nujol) νmax: 3540, 3350, 3250, 1705, 1680, 1660, 1650, 1610 cm⁻¹.

N.M.R. δppm (CDCl₃): 1.10 (9H, s), 2.3 (2H, s), 4.83 (3H, s), 4.9 (3H,s), 7.93 (2H, s), 8.3 (2H, m), 8.8 (1H, s), 9.3 (1H, d, J=12.0 Hz), 11.9(1H, d, J=12.0 Hz).

EXAMPLE 29

A mixture of 4-amino-6-(3,3-dimethylbutyramido)quinazoline (12.2 g),diethyl ethoxymethylenepropandioate (15.3 g) and N,N-dimethylformamide(50 ml) was stirred at 150° C. for 2 hours. The reaction mixture wascooled to ambient temperature. After adding water, the resultant mixturewas extracted with chloroform. The chloroform layer was washed twicewith water and once with saturated aqueous sodium chloride, dried overanhydrous magnesium sulfate and concentrated under reduced pressure togive a residue, to which was added ethyl acetate. Insoluble materialswere separated by filtration and dried to give ethyl4-oxo-10-(3,3-dimethylbutanamido)-4H-pyrimido[1,2-c]quinazoline-3-carboxylate(4.7 g) melting at 253°-254° C. Further, the filtrate was concentratedunder reduced pressure to give a residue, which was recrystallized froma mixture of ethyl acetate and hexane to give crystalline diethyl[{6-(3,3-dimethylbutyramido)-4-quinazolinylamino}methylene]propanedioate(10.1 g).

mp: 133°-135° C.

IR (Nujol) νmax: 3350, 1695, 1640, 1625, 1610 cm⁻¹.

N.M.R. δppm (CDCl₃): 1.15 (9H, s), 1.38 (3H, t, J=6.0 Hz), 1.40 (3H, t,J=6.0 Hz), 2.35 (2H, s), 4.33 (2H, q, J=6.0 Hz), 4.43 (2H, q, J=6.0 Hz),7.80 (1H, s), 7.9-8.1 (2H, m), 8.20 (1H, s), 8.86 (1H, s), 9.33 (1H, d,J=12.0 Hz), 12.0 (1H, d, J=12.0 Hz).

Anal. calcd. for C₂₂ H₂₈ N₄ O₅ : C 61.66; H 6.54; N 13.08. Found: C61.51; H 6.49; N 13.19.

EXAMPLE 30

A mixture of 4-amino-6-pivalamidoquinazoline (2.44 g), dimethylmethoxymethylenepropanedioate (2.61 g) and N,N-dimethyl formamide (10ml) was stirred at 100° C. for an hour. After cooling to ambienttemperature, to the mixture was added water. The mixture was stirred togive crystals, which was filtered off and purified by a columnchromatography on silicagel [developing solvent: a mixture of ethylacetate and chloroform (1:2)] to give crystals (3.48 g), which weredissolved in chloroform. To the solution was added activated charcoal.The mixture was filtered and the filtrate was concentrated under reducedpressure to give crystals, which were recrystallized from ethyl acetateto give crystalline dimethyl[{6-pivalamido-4-quinazolinylamino}methylene]propanedioate (2.3 g).

mp: 189°-190° C.

IR (Nujol) νmax: 3400, 3350, 1750, 1690, 1630, 1615 cm⁻¹.

N.M.R. δppm (CDCl₃): 1.4 (9H, s), 3.8 (3H, s), 3.93 (3H, s), 7.85 (1H,s), 8.00 (2H, m), 8.45 (1H, s), 8.9 (1H, s), 9.4 (1H, d, J=12.0 Hz).

Anal. Calcd. for C₁₉ H₂₂ N₄ O₅ : C 59.06; H 5.74; N 14.50. Found: C58.99; H 5.53; N 14.21.

EXAMPLE 31

A mixture of 4-amino-6-methanesulfonamidoquinazoline (2.0 g), diethylethoxymethylenepropanedioate (3.15 g) and N,N-dimethylformamide (16 ml)was stirred at 140° C. for an hour and a half. To the reaction mixturewas added diethyl ethoxymethylenepropanedioate (1.57 g). The reactionmixture was stirred for an hour and cooled to ambient temperature. Tothe mixture was added water to five crystals, which were filtered offand dissolved in a mixture of chloroform and methanol. The solution wasdried over anhydrous magnesium sulfate and concentrated under reducedpressure to give a residue, to which was added chloroform. The mixturewas heated and insoluble materials were filtered off to give crystallineethyl4-oxo-10-methanesulfonamido-4H-pyrimido[1,2-c]quinazoline-3-carboxylate(0.12 g) melting at 310°-312° C. Further, the filtrate was concentratedunder reduced pressure and allowed to stand at ambient temperature togive crystals (1.63 g), which were purified by a column chromatographyon silica gel (60 g) (developing solvent: 3% methanol-chloroformsolution). The crystals were dissolved in 10% methanol-chloroformsolution. The solution was treated with activated charcoal andconcentrated under reduced pressure. The residue was recrystallized fromchloroform to give crystalline diethyl[{6-methanesulfonamido-4-quinazolinylamino}methylene]propanedioate (1.45g).

mp: 200°-202° C.

IR (Nujol) νmax: 3500, 3210, 1720, 1690, 1675, 1640, 1625, 1600 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 1.3 (3H, t, J=7.0 Hz), 1.35 (3H, t, J=7.0 Hz),3.16 (3H, s), 4.25 (2H, q, J=7.0 Hz), 4.38 (2H, q, J=7.0 Hz), 7.8-8.1(3H, m), 8.9 (1H, s), 9.2 (1H, d, J=12.0 Hz), 10.53 (1H, s), 11.55 (1H,d, J=12.0 Hz).

EXAMPLE 32

A mixture of 4-amino-6-methanesulfonamidoquinazoline (6.89 g), diethylethoxymethylenepropanediate (15.5 g) and N,N-dimethylformamide (55 ml)was stirred at 155° C. for 2.5 hours. The reaction mixture was cooled toambient temperature. To the mixture was added water to giveprecipitates, which are separated by filtration and washed with water.To the crystals was added a mixture of methanol and chloroform (1:4)(400 ml). After stirring under heating, insoluble materials (6.95 g)were filtered off and recrystallized from N,N-dimethylformamide to givecrystalline ethyl4-oxo-10-methanesulfonamido-4H-pyrimido[1,2-c]quinazoline-3-carboxylate(5.76 g).

mp: 310°-312° C.

IR (Nujol) νmax: 3200, 3050, 1725, 1665, 1610 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 1.3 (3H, t, J=7.0 Hz), 3.1 (3H, s), 4.3 (2H, q,J=7.0 Hz), 7.7-8.1 (2H, m), 8.56 (1H, d, J=2.0 Hz), 8.9 (1H, s), 9.4(1H, s), 10.5 (1H, m).

Anal. Calcd. for C₁₅ H₁₄ N₄ O₅ S: C 49.72; H 3.89; N 15.46; S 8.85.Found: C 49.88; H 3.96; N 15.52; S 8.71.

EXAMPLE 33

A mixture of 4-amino-6-methanesulfonamidoquinazoline (6.68 g), dimethylmethoxymethylenepropanedioate (6.35 g) and N,N-dimethylformamide (27 ml)was stirred at 100° C. for an hour. The reaction mixture was cooled toambient temperature. To the mixture was added water to give crystals,which were filtered off and recrystallized from N,N-dimethylformamide togibe crystalline dimethyl[{6-methanesulfonamido-4-quinazolinylamino}methylene]propanedioate (7.20g).

mp: 284°-287° C.

IR (Nujol) νmax: 3230, 3130, 1730, 1690, 1650, 1625, 1600 cm⁻¹.

N.M.R. δppm (DMSO₄ -d₆): 3.12 (3H, s), 3.76 (3H, s), 3.90 (3H, s),7.7-8.1 (4H, m), 8.86 (1H, s), 9.26 (1H, m).

EXAMPLE 34

(1) A solution of diethyl[(6-nitro-4-quinazolinylamino)methylene]propanedioate (10.8 g) inN,N-dimethylformamide (325 ml) was shaken with 10% palladium on carbon(3.6 g) in hydrogen atmosphere at ambient temperature. After theabsorption of hydrogen was finished, the catalyst was removed byfiltration. The filtrate was concentrated under reduced pressure to givea residue, to which was added benzene. The mixture was concentratedunder reduced pressure to give crude crystals of diethyl[(6-amino-4-quinazolinylamino)methylene]propanedioate.

(2) A mixture of diethyl[(6-amino-4-quinazolinylamino)methylene]propanedioate as obtained above,pyridine (3.32 g) and dry methylene chloride (200 ml) was stirred underice-cooling. To the mixture was added dropwise a solution of3,3-dimethylbutyryl chloride (4.8 g) in methylene chloride (10 ml)during 50 minutes under ice-cooling. The reaction mixture was stirredunder ice-cooling for 3 hours and 10 minutes. To the mixture was addedice-water. After stirring, the mixture was extracted with methylenechloride. The organic layer was washed with water and saturated aqueoussodium chloride, dried over anhydrous magnesium sulfate and concentratedunder reduced pressure to give a residue, which was subjected to acolumn chromatography on silica gel (200 g) (Developing solvent:methylene chloride) to give fraction A and fraction B. The fraction Awas concentrated under reduced pressure to give crystals (4.28 g), whichwere dissolved in ethyl acetate, treated with activated charcoal andrecrystallized to give crystalline diethyl[{6-(3,3-dimethylbutyramido)-4-quinazolinylamino}methylene]propanedioate(2.29 g).

mp: 133°-135° C.

IR (Nujol) νmax: 3350, 1695, 1640, 1625, 1610 cm⁻¹.

N.M.R. δppm (CDCl₃): 1.15 (9H, s), 1.38 (3H, t, J=6.0 Hz), 1.40 (3H, t,J=6.0 Hz), 2.35 (2H, s), 4.33 (2H, q, J=6.0 Hz), 4.43 (2H, q, J=6.0 Hz),7.80 (1H, s), 7.9-8.1 (2H, m), 8.2 (1H, s), 8.86 (1H, s), 9.33 (1H, d,J=12.0 Hz), 12.0 (1H, d, J=12.0 Hz).

Anal. Calcd. for C₂₂ H₂₈ N₄ O₅ : C 61.66; H 6.54; N 13.08. Found: C61.51; H 6.49; N 13.19.

Further, the fraction B was concentrated under reduced pressure to givecrystals (2.6 g), which were dissolved in hexane, treated with activatedcharcoal and recrystallized to give crystals (1.48 g). A part (1.25 g)of the crystals was purified by a column chromatography on silica gel(20 g) and recrystallized from hexane to give diethyl[[6-{bis(3,3-dimethylbutyryl)amino}-4-quinazolinylamino]methylene]propanedioate(0.9 g).

mp: 100°-102° C.

IR (Nujol) νmax: 3200, 1775, 1730, 1710, 1645, 1625, 1610, 1560 cm⁻¹.

N.M.R. δppm (CDCl₃): 1.03 (9H, s), 1.06 (9H, s), 1.33 (3H, t, J=7.0 Hz),1.40 (3H, t, J=7.0 Hz), 2.30 (2H, s), 2.45 (2H, s), 4.3 (2H, q, J=7.0Hz), 4.4 (2H, q, J=7.0 Hz), 7.9-8.15 (3H, m), 9.25 (1H, s), 9.8 (1H, d,J=12.0 Hz)

Anal. Calcd. for C₂₈ H₃₈ N₄ O₆.H₂ O: C 61.74; H 7.40; N 10.60. Found: C61.81; H 7.19; N 10.29.

EXAMPLE 35

A mixture of dimethyl[{6-pivalamido-4-quinazolinylamino}methylene]propanedioate (24.5 g) anddiphenyl ether (150 ml) was heated at 260° C. for 20 minutes and cooledto ambient temperature. To the reaction mixture was added hexane to givecrystals, which were filtered off, washed with hexane and dissolved inchloroform (400 ml) under heating. Insoluble materials were removed byfiltration. The filtrate was concentrated under reduced pressure to 200ml and allowed to stand under cooling. The precipitated crystals werefiltered off and washed with chloroform to give crystalline methyl4-oxo-10-pivalamido-4H-pyrimido[1,2-c]quinazoline-3-carboxylate (18.29g). The mother liquor was concentrated under reduced pressure to givecrystals, which are purified by a column chromatography on silica gel(50 g) (Developing solvent: 5% methanol-chloroform solution) andrecrystallized from chloroform to give the same object compound (3.2 g).

mp: 239°-240° C.

IR (Nujol) νmax: 3380, 1715, 1685, 1610 cm⁻¹.

N.M.R. δppm (CDCl₃): 1.4 (9H, s), 3.96 (3H, s), 7.85 (1H, s), 8.0 (1H,d, J=9.0 Hz), 8.4 (1H, dd, J=3.0 and 9.0 Hz), 8.9 (1H, d, J=3.0 Hz),9.05 (1H, s), 9.63 (1H, s).

EXAMPLE 36

A mixture of dimethyl[{6-methanesulfonamido-4-quinazolinylamino)methylene]propanedioate (7.2g) and diphenyl ether (43 ml) was stirred at 250° C. for 15 minutes andthen cooled to ambient temperature to give crystals, which were filteredoff and washed with a mixture of chloroform and methanol to givecrystalline methyl4-oxo-10-methanesulfonamido-4H-pyrimido[1,2-c]quinazoline-3-carboxylate(4.72 g).

mp: 293°-296° C.

IR (Nujol) νmax: 3220, 1725, 1670, 1608 cm⁻¹.

EXAMPLE 37

A mixture of diethyl[{6-(3,3-dimethylbutyramido-4-quinazolinylamino}methylene]propandioate(13.1 g) and diphenyl ether (79 ml) was stirred at 250° C. for 15minutes and cooled to ambient temperature. To the mixture was addedhexane. The resultant mixture was stirred to give precipitates, whichwere separated by filtration and dissolved in a mixture of chloroformand methanol. To the mixture was added charcoal and the mixture wasstirred and filtered. The filtrate was concentrated under reducedpressure to give crystals, which were recrystallized from a mixture ofchloroform and hexane to give crystalline ethyl4-oxo-10-(3,3-dimethylbutyramido)-4H-pyrimido[1,2-c]quinazoline-3-carboxylate(9.15 g).

mp: 253°-254° C.

IR (Nujol) νmax: 3350, 1715, 1680, 1615, 1585, 1565, 1505 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 1.1 (9H, s), 1.3 (3H, t, J=8.0 Hz), 2.26 (2H, s),4.3 (2H, q, J=8.0 Hz), 7.9 (1H, d, J=9.0 Hz), 8.16 (1H, dd, J=2.0 and9.0 Hz), 8.9 (1H, s), 9.15 (1H, d, J=2.0 Hz), 9.4 (1H, s), 10.36 (1H,s).

Anal. Calcd for C₂₀ H₂₂ N₄ O₄ : C 62.81; H 5.80; N 14.65. Found: C62.69; H 5.77; N 14.67.

EXAMPLE 38

A mixture of dimethyl[{6-(3,3-dimethylbutyramido)-4-quinazolinylamino}methylene]propanedioate(7.30 g) and diphenylether (44 ml) was stirred at 260° C. for 10 minutesand then cooled to ambient temperature. To the mixture was added hexaneto give crystals, which were filtered off and washed with hexane to givecrystalline methyl4-oxo-10-(3,3-dimethylbutyramido)-4H-pyrimido[1,2-c]quinazoline-3-carboxylate(6.28 g).

mp: 247°-249° C.

IR (Nujol) νmax: 3350, 1740, 1720, 1685, 1610 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 1.1 (9H, s), 2.33 (2H, s), 3.9 (3H, s), 7.96 (1H,d, J=9.0 Hz), 8.23 (1H, dd, J=2.0 and 9.0 Hz), 9.00 (1H, s), 9.22 (1H,s), 9.46 (1H, s), 10.43 (1H, s).

EXAMPLE 39

A mixture of methyl4-oxo-10-pivalamido-4H-pyrimido[1,2-c]quinazoline-3-carboxylate (1.27g), anhydrous lithium iodide (3.18 g) and dry pyridine (13 ml) wasstirred at 120° C. for 3 hours and then concentrated under reducedpressure to give a residue, which was dissolved in water. Insolublematerials were removed by filtration. The filtrate was adjusted to pH 1with conc. hydrochloric acid to give crystals, which were filtered offand washed with water. To the crude crystals was added methanol. Themixture was stirred and filtered to give crystals (1.0 g), which werewashed with a mixture of chloroform amd methanol to give crystalline4-oxo-10-pivalamido-4H-pyrimido[1,2-c]quinazoline-3-carboxyic acid (0.65g).

mp: 330°-332° C.

IR (Nujol) νmax: 3340, 1720, 1680, 1660, 1610 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 1.25 (9H, s), 7.9 (1H, d, J=9.0 Hz), 8.35 (1H,dd, J=2.0 and 9.0 Hz), 8.93 (1H, s), 9.13 (1H, d, J=2.0 Hz), 9.4 (1H,s), 9.75 (1H, s).

Anal. Calcd. for C₁₇ H₁₆ N₄ O₄ : C 59.99; H 4.74; N 16.46. Found: C59.49; H 4.60; N 16.39.

EXAMPLE 40

A mixture of methyl4-oxo-10-methanesulfonamido-4H-pyrimido[1,2-c]quinazoline-3-carboxylate(4.32 g), anhydrous lithium iodide (10.8 g) and dry pyridine (43 ml) wasstirred at 120° C. for 2 hours. The reaction mixture was concentratedunder reduced pressure to give a residue, which was dissolved in water(900 ml). Insoluble materials were removed by filtration. The aqueouslayer was adjusted to pH 5 with conc. hydrochloric acid to givecrystals, which were filtered off, suspended in a mixture of chloroformand methanol, stirred and filtered to give crystals, which were dried togive crystalline4-oxo-10-methanesulfonamido-4H-pyrimido[1,2-c]quinazoline-3-carboxylicacid (2.8 g).

mp: 319°-322° C.

IR (Nujol) νmax: 3550, 3450, 1695, 1680, 1605 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 3.20 (3H, s), 7.8-8.2 (2H, m), 8.65 (1H, d, J=2.0Hz), 9.0 (1H, s), 9.5 (1H, s), 10.56 (1H, s).

EXAMPLE 41

A mixture of methyl4-oxo-10-(3,3-dimethylbutyramido)-4H-pyrimido[1,2-c]quinazoline-3-carboxylate(6.0 g), anhydrous lithium iodide (15.0 g) and dry pyridine (60 ml) wasstirred at 120° C. for 2 hours. The reaction mixture was concentratedunder reduced pressure to give a residue, to which was added water. Themixture was filtered to give crystals, which were suspended in water(100 ml) and adjusted to pH 1-2 with con. hydrochloric acid to givecrystals, which were separated by filtration and dried to givecrystalline4-oxo-10-(3,3-dimethylbutyramido)-4H-pyrimido[1,2-c]quinazoline-3-carboxylicacid (2.5 g).

mp: 304°-306° C.

IR (Nujol) νmax: 3330, 1730, 1690, 1660, 1610 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 1.00 (9H, s), 2.26 (2H, s), 7.93 (1H, d, J=9.0Hz), 8.16 (1H, dd, J=2.0 and 9.0 Hz), 8.96 (1H, s), 9.20 (1H, d, J=2.0Hz), 9.43 (1H, s), 10.40 (1H, s).

EXAMPLE 42

A mixture of 4-amino-6-(2-ethylbutyramido)quinazoline (5.58 g), dimethylmethoxymethylenepropanedioate (5.62 g) and N,N-dimethylformamide (22 ml)was stirred at 100° C. for 1.5 hours. After cooling to ambienttemperature, water (90 ml) was added to the reaction mixture. Theresulting solid was separated by filtration, washed with water and driedto give dimethyl[[6-(2-ethylbutyramido)-4-quinazolinylamino]methylene]propanedioate(4.85 g).

m.p. 221°-225° C.

IR (Nujol), νmax: 3280, 1725, 1660, 1630, 1610, 1570, 1525 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 0.92 (6H, t, J=7.0 Hz), 1.3-1.8 (4H, m); 2.0-2.5(1H, m), 3.76 (3H, s), 3.92 (3H, s), 7.9 (1H, d, J=10.0 Hz), 8.2 (1H,dd, J=2.0, 10.0 Hz), 8.56 (1H, d, J=2.0 Hz), 8.83 (1H, s), 9.23 (1H, d,J=12.0 Hz), 10.5 (1H, s), 11.52 (1H, d, J=12.0 Hz).

EXAMPLE 43

A mixture of 4-amino-6-(2-methylpropionamido)quinazoline (6.2 g) anddimethyl methoxymethylenepropanedioate (7.01 g) in N,N-dimethylformamide(25 ml) was stirred at 100° C. for 1.5 hours and cooled to roomtemperature. Water was added to the reaction mixture. The resultingsolid was separated by filtration, washed with water and dried to givedimethyl[[6-(2-methylpropionaido)-4-quinazolinylamino]methylene]propanedioate(8.9 g). Recrystallization from ethyl acetate gave pure crystals meltingat 212°-214° C.

IR (Nujol), νmax: 3270, 1710, 1660, 1630, 1610, 1560, 1530 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 1.20 (6H, d, J=7.0 Hz), 2.40-2.66 (1H, m), 3.76(3H, s), 3.90 (3H, s), 7.93 (1H, d, J=9.0 Hz), 8.08 (1H, d, J=9.0 Hz),8.4 (1H, s), 8.73 (1H, s), 9.13 (1H, d, J=12.0 Hz), 10.4 (1H, s), 11.13(1H, d, J=12.0 Hz).

Anal. Calcd. for C₁₈ H₂₀ N₄ O₅ : C, 58.06; H, 5.41; N, 15.03. Found: C,58.14; H, 5.39; N, 15.19.

EXAMPLE 44

A mixture of 4-amino-6-cyclohexanecarboxyamidoquinazoline (8.85 g) anddimethyl methoxymethylenepropanedioate (8.55 g) in N,N-dimethylformamide(35 ml) was stirred at 100° C. for 1 hour. After cooling to ambienttemperature, water was added to the reaction mixture. The resultingsolid was collected by filtration, washed with water and dried. Thesolid was chromatographed on silica gel with 1% methanol-chloroform andrecrystallized from chloroform to give a crystalline solid (6.13 g). Thesolid is a mixture of dimethyl[[6-cyclohexanecarboxamido-4-quinazolinylamino]methylene]propanedioateand methyl4-oxo-10-cyclohexanecarboxamido-4H-pyrimido[1,2-C]quinazoline-3-carboxylicin the ratio of about 2:1.

mp. 210°-212° C.

IR (Nujol) νmax: 3330, 1735, 1710, 1682, 1662, 1625, 1608 cm⁻¹.

EXAMPLE 45

A mixture of 4-amino-6-(3-cyclopentylpropionamido)quinazoline (7.05 g)and dimethyl methoxymethylenepropanedioate (6.48 g) inN,N-dimethylformamide (28 ml) was stirred at 100° C. for 1 hour and 10minutes. After cooling to ambient temperature, water was added to thereaction mixture. The resulting solid was separated by filtration,washed with water, and dried. The crude crystals were dissolved in amixture of chloroform and methanol, treated with activated charcoal, andevaporated under reduced pressure until crystallizaton began. Aftercooling, the resulting solid was collected, washed with methanol andwith dichloromethane, and dried. There was obtained crystalline methyl4-oxo-10-(3-cyclopentylpropionamido)-4H-pyrimido[1,2-C]quinazoline-3-carboxylate(2.16 g). The filtrate was evaporated under reduced pressure to give aresidue which was chromatographed on silica gel with 1%methanol-dichloromethane. The first fractions contained methyl4-oxo-10-(3-cyclopentylpropionamido)-4H-pyrimido[1,2-C]quinazoline-3-carboxylate(1.9 g). The second fractions contained dimethyl[[6-(3-cyclopentylpropionamido)-4-quinazolinylamino]methylene]propanedioate(5.16 g).

mp. 193°-197° C.

IR (Nujol) νmax: 3340, 1745, 1708, 1690, 1660, 1630, 1620 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 0.8-2.1 (11H, m), 2.23 (2H, t, J=7.0 Hz), 3.75(3H, s), 3.90 (3H, s), 7.78 (1H, d, J=9.0 Hz), 8.05 (1H, d, J=9.0 Hz),8.36 (1H, s), 8.73 (1H, s), 9.11 (1H, d, J=12.0 Hz), 10.40 (1H, s),11.40 (1H, d, J=12.0 Hz).

EXAMPLE 46

A mixture ofdimethyl[[6-(2-ethylbutyramido)-4-quinazolinylamino]methylene]propanedioate(5.3 g) and diphenyl ether (32 ml) was heated at 255° C. for 15 minutesand cooled to ambient temperature. Hexane was added to the reactionmixture. The resulting crystals were filtered off, washed with hexaneand dried. The crude crystals were dissolved in a mixture of chloroformand methanol (10:1) under heating. Insoluble materials were removed byfiltration. The filtrate was concentrated under reduced pressure to givecrystals, which are recrystallized from a mixture of chloroform andhexane to give methyl4-oxo-10-(2-ethylbutyramido)-4H-pyrimido[1,2-C]quinazoline-3-carboxylate(3.81 g).

mp. 239°-240° C.

IR (Nujol) νmax: 3350, 1730, 1690, 1665, 1610, 1490 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 0.92 (6H, t, J=8.0 Hz), 1.24-1.84 (4H, m),2.12-2.42 (1H, m), 3.84 (3H, s), 7.92 (1H, d, J=8.0 Hz), 8.18 (1H, dd,J=2.0, 8.0 Hz), 8.88 (1H, s), 9.12 (1H, d, J=2.0 Hz), 9.38 (1H, s), 10.4(1H, s).

Anal. Calcd. for C₁₉ H₂₀ N₄ O₄ : C, 61.94; H, 5.47; N, 15.21. Found: C,61.71; H, 5.55; N, 15.38.

EXAMPLE 47

A mixture of dimethyl[[6-(2-methylpropionamido)-4-quinazolinylamino]methylene]propanedioate(8.4 g) in diphenyl ether (42 ml) was stirred at 255° C. for 15 minutes.The reaction mixture was cooled to ambient temperature to give crystalswhich were filtered off, washed with hexane and dried. There wereobtained 6.9 g of the crude crystals. The crude crystals were dissolvedin a mixture of chloroform and methanol (4:1) under heating. Insolublematerials were removed by filtration. The filtrate was concentratedunder reduced pressure to about 150 ml. After cooling, there wasobtained crystalline methyl4-oxo-10-(2-methylpropionamido)-4H-pyrimido[1,2-C]quinazoline-3-carboxylate(5.85 g).

mp. 275°-277° C.

IR (Nujol) νmax: 3345, 1700, 1670, 1610, 1580, 1560 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 1.16 (6H, d, J=7 Hz), 2.4-2.8 (1H, m), 3.86 (3H,s), 7.93 (1H, d, J=9 Hz), 8.22 (1H, dd, J=2, 9 Hz), 8.93 (1H, s), 9.2(1H, d, J=2 Hz), 9.43 (1H, s), 10.43 (1H, s).

Anal. Calcd. for C₁₇ H₁₆ N₄ O₄ : C, 59.99; H, 4.74; N, 16.46. Found: C,59.73; H, 4.58; N, 16.37.

EXAMPLE 48

A mixture of dimethyl[[6-cyclohexanecarboxamido-4-quinazolinylamino]methylene]propanedioate(4 g) and diphenyl ether (31 ml) was stirred at 260° C. for 15 minutes.After cooling to ambient temperature, the resulting solid was collectedby filtration, washed with hexane and dried. There was obtained methyl4-oxo-10-cyclohexanecarboxamido-4H-pyrimido[1,2-C]quinazoline-3-carboxylate(3.6 g).

mp. 250°-251° C.

N.M.R. δppm (DMSO-d₆): 1.1-2.1 (10H, m), 2.2-2.8 (1H, m), 3.86 (3H, s),7.9 (1H, d, J=9.0 Hz), 8.18 (1H, dd, J=2.0, 9.0 Hz), 8.9 (1H, s), 9.13(1H, d, J=2.0 Hz), 9.4 (1H, s), 10.36 (1H, s).

Anal. Calcd. for C₂₀ H₂₀ N₄ O₄ : C, 63.15; H, 5.30; N, 14.73. Found: C,63.12; H, 5.24; N, 14.78.

EXAMPLE 49

A mixture of dimethyl[[6-(3-cyclopentylpropionamido)-4-quinazolinylamino]methylene]propanedioate(6.9 g) in diphenyl ether (53 ml) was stirred at 255° C. for 15 minutesand cooled to ambient temperature. The resulting solid was collected,washed with hexane and dried. There was obtained methyl4-oxo-10-(3-cyclopentylpropionamido)-4H-pyrimido[1,2-C]quinazoline-3-carboxylate(4.3 g).

mp. 244°-247° C.

IR (Nujol) νmax: 3350, 1712, 1682, 1612 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 1.0-2.0 (11H, m), 2.3 (2H, m), 3.85 (3H, s),7.8-8.2 (2H, m), 8.93 (1H, s), 9.20 (1H, s), 9.43 (1H, s), 10.50 (1H,s).

EXAMPLE 50

A mixture of methyl4-oxo-10-(2-ethylbutyramido)-4H-pyrimido[1,2-C]quinazoline-3-carboxylate(3.2 g), anhydrous lithium iodide (8.0 g) and dry pyridine (32 ml) wasstirred at 120° C. for 1.5 hours. The reaction mixture was concentratedunder reduced pressure to give a residue, which was dissolved in water.Insoluble materials were removed by filtration. The aqueous layer wasadjusted to pH 1-2 with conc. hydrochloric acid to give crystals, whichwere separated by filtration and dried. The crude crystals were washedwith methanol three times and recrystallized from acetonitrile to give4-oxo-10-(2-ethylbutyramido)-4H-pyrimido[1,2-C]quinazoline-3-carboxylicacid (0.7 g).

mp. 295°-298° C.

N.M.R. δppm (DMSO-d₆): 0.96 (6H, t, J=7.0 Hz), 1.3-1.9 (4H, m), 2.0-2.6(1H, m), 8.0 (1H, d, J=9.0 Hz), 8.26 (1H, dd, J=2.0, 9.0 Hz), 9.0 (1H,s), 9.26 (1H, d, J=2.0 Hz), 9.5 (1H, s), 10.5 (1H, s).

EXAMPLE 51

A mixture of methyl4-oxo-10-(2-methylpropionamido)-4H-pyrimido[1,2-C]quinazoline-3-carboxylate(5.42 g) and anhydrous lithium iodide (13.55 g) in dry pyridine (54 ml)was stirred at 100° C. for 1.5 hours. The reaction mixture was cooled togive crystals which were collected by filtration and washed withpyridine. The crystals were suspended in water (200 ml). The suspensionwas adjusted to pH 2.5-3.0 with conc. hydrochloric acid to give yellowcrystals, which were separated by filtration, washed with water anddried. The crude crystals were washed with a mixture of chloroform andmethanol (1:1) two times and dried. There was obtained crystalline4-oxo-10-(2-methylpropionamido)-4H-pyrimido[1,2-C]quinazoline-3-carboxylicacid (3.80 g).

mp. 312°-314° C.

IR (Nujol) νmax: 3350, 1730, 1698, 1655, 1620 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 1.15 (6H, d, J=7.0 Hz), 2.4-2.8 (1H, m), 7.9 (1H,d, J=9.0 Hz), 8.2 (1H, dd, J=2.0, 9.0 Hz), 8.93 (1H, s), 9.15 (1H, d,J=2.0 Hz), 9.36 (1H, s), 10.4 (1H, s).

Anal. Calcd. for C₁₆ H₁₄ N₄ O₄ : C, 58.89; H, 4.32 N, 17.17. Found: C,58.73; H, 4.36 N, 17.22.

EXAMPLE 52

A mixture of methyl4-oxo-10-cyclohexanecarboxamido-4H-pyrimido[1,2-C]quinazoline-3-carboxylate(4.7 g) and anhydrous lithium iodide (11.75 g) in dry pyridine (47 ml)was stirred at 100° C. for 1 hour and 20 minutes and cooled to ambienttemperature. The resulting solid was collected by filtration and washedwith ethanol. The solid was suspended in water (100 ml). The suspensionwas adjusted to pH 1-2 with conc. hydrochloric acid to give yellowcrystals which were separated by filtration, washed with water anddried. The crude crystals were washed with a mixture of chloroform andmethanol and dried. There was obtained4-oxo-10-cyclohexanecarboxamido-4H-pyrimido[1,2-C]quinazoline-3-carboxylicacid (2.75 g).

mp. 311°-314° C.

IR (Nujol) νmax: 3330, 3020, 1740, 1710, 1660, 1610, 1580 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 1.0-2.2 (10H, m), 2.23-2.8 (1H, m), 7.93 (1H, d,J=9.0 Hz), 8.2 (1H, dd, J=9.0, 2.0 Hz), 8.96 (1H, s), 9.2 (1H, d, J=2.0Hz), 9.45 (1H, s), 10.4 (1H, s).

Anal. Calcd. for C₁₉ H₁₈ N₄ O₄ : C, 62.28; H, 4.95; N, 15.29. Found: C,61.59; H, 4.91; N, 15.20.

EXAMPLE 53

A mixture of methyl4-oxo-10-(3-cyclopentylpropionamido)-4H-pyrimido[1,2-C]quinazoline-3-carboxylate(5.72 g) and anhydrous lithium iodide (14.3 g) in dry pyridine (59 ml)was stirred at 120° C. for 1.5 hours. The reaction mixture wasconcentrated under reduced pressure to give a crystalline residue, whichwas suspended in water (100 ml). The suspension was adjusted to pH 1.7with conc. hydrochloric acid to yield yellow crystals, which wereseparated by filtration, washed with water and dried. Recrystallizationfrom N,N-dimethylformamide gave crystalline4-oxo-10-(3-cyclopentylpropionamido)-4H-pyrimido[1,2-C]quinazoline-3-carboxylicacid (4.4 g).

mp. 279°-283° C.

IR (Nujol) νmax: 3350, 1730, 1690, 1668, 1610, 1600, 1580 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 0.7-2.1 (11H, m), 2.4 (2H, m), 7.90 (2H, d, J=8Hz), 8.16 (1H, dd, J=8.0, 2.0 Hz), 8.93 (1H, s), 9.13 (1H, d, J=2.0 Hz),9.23 (1H, s), 10.41 (1H, s).

EXAMPLE 54

A mixture of 4-amino-6-(2-ethylbutyramido)quinazoline (0.9 g) anddiethyl ethoxymethylenepropanedioate (0.95 g) in N,N-dimethylformamide(4 ml) was stirred at 100° C. for 2 hours and 40 minutes. Water wasadded to the reaction mixture. The resulting crystals were collected,washed with water and dried. The crude crystals were chromatographed onsilica gel with 20% ethyl acetate-chloroform and recrystallized from amixture of ethyl acetate, chloroform and hexane to give crystalinediethyl[[6-(2-ethylbutyramido)-4-quinazolinylamino]methylene]propanedioate (1.1g).

mp: 191°-194° C.

IR (Nujol) νmax: 3280, 1720, 1658, 1628, 1610, 1570 cm⁻¹.

NMR δppm (DMSO-d₆): 0.92 (6H, t, J=7 Hz), 1.28 (3H, t, J=7 Hz), 1.32(3H, t, J=7 Hz), 1.56 (4H, m), 2.36 (1H, m), 4.2 (2H, q, J=7 Hz), 4.36(2H, q, J=7 Hz), 7.88 (1H, d, J=9 Hz), 8.16 (1H, d, J=9 Hz), 8.48 (1H,s), 8.8 (1H, s), 9.16 (1H, d, J=12 Hz), 10.44 (1H, s), 11.4 (1H, d, J=12Hz).

EXAMPLE 55

A mixture of diethyl[[6-(2-ethylbutyramido)-4-quinazolinylamino]methylene]propanedioate (0.6g) in diphenyl ether (3 ml) was stirred at 250° C. for 15 minutes andcooled to ambient temperature. The resulting crystals were filtered,washed with ethyl acetate and dried. There was obtained ethyl4-oxo-10-(2-ethylbutyramido)-4H-pyrimido[1,2-C]quinazoline-3-carboxylate(0.5 g).

mp: 220°-222° C.

IR (Nujol) νmax: 3340, 1715, 1700, 1668 cm⁻¹.

NMR δppm (DMSO-d₆): 0.88 (6H, t, J=7 Hz), 1.32 (3H, t, J=7 Hz), 1.56(4H, m), 2.35 (1H, m), 4.3 (2H, q, J=7 Hz), 7.92 (1H, d, J=9 Hz), 8.16(1H, d, J=9 Hz), 8.88 (1H, s), 9.16 (1H, broad d), 9.38 (1H, s), 10.4(1H, s).

EXAMPLE 56

A mixture of 4-amino-6-(3-cyclopentylpropionamido)quinazoline (4.4 g)and diethyl ethoxymethylenepropanedioate (5.5 g) inN,N-dimethylformamide (20 ml) was stirred at 100° C. for 3 hours. To thereaction mixture was added water. The resulting crystals were collectedby filtration, washed with water, and suspended in dichloromethane underheating. After the suspension was cooled to ambient temperature, theresulting crystals were collected by filtration and washed withdichloromethane. There was obtained ethyl4-oxo-10-(3-cyclopentylpropionamido)-4H-pyrimido[1,2-C]quinazoline-3-carboxylate(2.4 g). The filtrate was concentrated to 1/4 of its original volume andcooled to 0° C. to yield an additional 0.37 g of the same product. Thecryde substance (2.77 g) obtained above was chromatographed on silicagel with 2% methanoldichloromethane. The product was recrystallized froma mixture of methanol and dichloromethane to give crystalline pureproduct (2.45 g).

mp: 241°-246° C.

IR (Nujol) νmax: 3350, 1725, 1685, 1672, 1615, 1582, 1560 cm⁻¹.

The mother liquor was chromatographed on silica gel with 1.5%methanol-chloroform to give an oil (1.15 g), which was crystallized froma mixture of ethyl acetate and hexane. There was obtained diethyl[[6-(3-cyclopentylpropionamido)-4-quinazolinylamino]methylene]propanedioate(0.82 g).

mp: 155°-158° C.

IR (Nujol) νmax: 3280, 1730, 1660, 1615, 1608, 1568, 1540 cm⁻¹.

NMR δppm (DMSO-d₆): 1.30 (3H, t, J=7 Hz), 1.32 (3H, t, J=7 Hz), 0.9-2.0(11H, m), 2.36 (2H, m), 4.20 (2H, q, J=7 Hz), 4.33 (2H, q, J=7 Hz), 7.80(1H, d, J=9 Hz), 8.06 (1H, d, J=9 Hz), 8.36 (1H, br s), 8.73 (1H, s),9.10 (1H, d, J=12 Hz), 10.36 (1H, s), 11.5 (1H, d, J=12 Hz).

EXAMPLE 57

A mixture of 4-amino-6-(2,3-dimethylpentanamido)quinazoline (6.75 g) anddimethyl methoxymethylene-propanedioate (6.48 g) inN,N-dimethylformamide (20 ml) was stirred at 100° C. for 1 hour andcooled to ambient temperature. Water was added to the reaction mixture.The resulting solid was separated by filtration, washed with water, anddried. There was obtained dimethyl[[6-(2,3-dimethylpentanamido)-4-quinazolinylamino]methylene]propanedioate(6.58 g). A portion of the crude product was chromatographed on silicagel with chloroform and ethyl acetate (3:1) and recrystallized fromethyl acetate to give analytically pure dimethyl[[6-(2,3-dimethylpentanamido)-4-quinazolinylamino]methylene]propanedioate(0.45 g).

mp: 216°-217° C.

IR (Nujol) νmax: 3270, 1725, 1660, 1630, 1610, 1565, 1540, 1500 cm⁻¹.

NMR δppm (DMSO-d₆): 0.7-2.0 (12H, m), 2.2-2.8 (1H, m), 3.8 (3H, s), 3.93(3H, s), 7.93 (1H, d, J=9 Hz), 8.2 (1H, dd, J=2,9 Hz), 8.55 (1H, d, J=2Hz), 8.85 (1H, s), 9.23 (1H, d, J=12 Hz), 10.43 (1H, s), 11.6 (1H, d,J=12 Hz).

Anal. Calcd for C₂₁ H₂₆ N₄ O₅ : C, 60.85; H, 6.32; N, 13.52. Found: C,61.16; H, 6.15; N, 13.56.

EXAMPLE 58

A mixture of dimethyl[[6-(2,3-dimethylpentanamido)-4-quinazolinylamino]methylene]propanedioate(5.75 g) in diphenyl ether (28 ml) was stirred at 255° C. for 15 minutesand cooled to ambient temperature. The resulting solid was collected byfiltration, washed with hexane, and dried. The crude crystals werechromatographed on silica gel with 4% methanol-chloroform. The productwas recrystallized from a mixture of methanol and chloroform. There wasobtained methyl4-oxo-10-(2,3-dimethylpentanamido)-4H-pyrimido[1,2-C]quinazoline-3-carboxylate(0.4 g). Concentration of the mother liquor gave a crystalline residue,which was recrystallized from a mixture of chloroform and hexane to giveadditional 4.25 g of the same product.

mp: 220°-221° C.

IR (Nujol) νmax: 3350, 1715, 1690, 1620, 1585, 1565, 1510 cm⁻¹.

NMR δppm (DMSO-d₆): 0.7-2.0 (12H, m), 2.2-2.7 (1H, m), 3.83 (3H, s), 7.9(1H, d, J=9 Hz), 8.2 (1H, dd, J=2, 9 Hz), 8.9 (1H, s), 9.33 (1H, d, J=2Hz), 9.4 (1H, s), 10.36 (1H, s).

Anal. Calcd. for C₂₀ H₂₂ N₄ O₄ : C, 62.81; H, 5.80; N, 14.65. Found: C,62.80; H, 5.55; N, 14.66.

EXAMPLE 59

A mixture of methyl4-oxo-10-(2,3-dimethylpentanamido)-4H-pyrimido[1,2-C]quinazoline-3-carboxylate(3.4 g) and anhydrous lithium iodide (8.5 g) in dry pyridine (34 ml) wasstirred at 100° C. for 1 hour and 20 minutes. The reaction mixture wasconcentrated under reduced pressure. Water was added to the residue togive precipitates, which were collected by filtration and washed withwater. The resulting crystals were suspended in water. The suspensionwas adjusted to pH 1-2 with conc. hydrochloric acid to give yellowcrystals, which were separated by filtration, washed with water, anddried. The crude crystals (3.85 g) were dissolved in a mixture ofchloroform and methanol under heating. The solution was filtered toremove insoluble materials. The filtrate was concentrated under reducedpressure to 40 ml and cooled in an ice bath. The resulting crystals werecollected by filtration and suspended in a mixture of chloroform andmethanol under heating. After the suspension was cooled to ambienttemperature, the crystals were filtered and dried. There was obtained4-oxo-10-(2,3-dimethylpentanamido)-4H-pyrimido[1,2-C]quinazoline-3-carboxylicacid (1.0 g).

mp: 286°-288° C.

IR (Nujol) νmax: 3330, 1740, 1700, 1660, 1610, 1580, 1520 cm⁻¹.

NMR δppm (DMSO-d₆): 0.7-1.9 (12H, m), 2.2-2.7 (1H, m), 7.9 (1H, d, J=9Hz), 8.18 (1H, dd, J=2, 9 Hz), 8.93 (1H, s), 9.16 (1H, d, J=2 Hz), 9.4(1H, s), 10.33 (1H, s), 12.3-13.1 (1H, broad S).

EXAMPLE 60

A mixture of 4-amino-7-pivalamidoquinazoline (10.5 g) and dimethylmethoxymethylenepropanedioate (10.9 g) in N,N-dimethylformamide (32 ml)was stirred at 100° C. for 1 hour and 25 minutes. After the reactionmixture was cooled to ambient temperature, water was added. Theresulting solid was separated by filtration, washed with water anddried. The crustals were recrystallized from a mixture of ethyl acetateand ethanol to give crystalline dimethyl[[7-pivalamido-4-quinazolinylamino]methylene]propanedioate (13.7 g).

mp: 183°-184° C.

IR (Nujol) νmax: 3470, 3250, 1705, 1680, 1650, 1620, 1540 cm⁻¹.

NMR δppm (DMSO-d₆): 1.32 (9H, s), 3.72 (3H, s), 3.82 (3H, s), 7.72 (1H,d, J=10 Hz), 7.92 (1H, dd, J=2, 10 Hz), 7.35 (1H, d, J=2 Hz), 8.72 (1H,s), 9.02 (1H, d, J=12 Hz), 9.66 (1H, s), 11.36 (1H, d, J=12 Hz).

EXAMPLE 61

a mixture of dimethyl[[7-pivalamido-4-quinazolinylamino]methylene]propanedioate (11.7 g) indiphenyl ether (58 ml) was stirred at 250° C. for 15 minutes and cooledto ambient temperature. Hexane was added to the reaction mixture. Theresulting crystals were collected by filtration, washed with hexane, anddried. The crystals were dissolved in a mixture of chloroform andethanol under heating. The solution was filtered to remove insolublematerials. The filtrate was concentrated under reduced pressure untilcrystallization began. After the solution was cooled to ambienttemperature, the resulting crystals were collected by filtration to givemethyl 4-oxo-9-pivalamido-4H-pirimido[1,2-C]quinazoline-3-carboxylate(5.1 g). Concentration of the mother liquor gave additional crystals ofthe same compound (3.4 g).

mp: 260°-262° C.

IR (Nujol) νmax: 3340, 1725, 1680, 1610, 1580, 1560, 1525 cm⁻¹.

NMR δppm (DMSO-d₆): 1.3 (9H, s), 3.8 (3H, s), 8.06 (1H, d, J=9 Hz), 8.36(1H, s), 8.64 (1H, d, J=9 Hz), 8.84 (1H, s), 9.42 (1H, s), 9.80 (1H, s).

EXAMPLE 62

A mixture of methyl4-oxo-9-pivalamido-4H-pyrimido[1,2-C]quinazoline-3-carboxylate (6.5 g)and anhydrous lithium iodide (16.25 g) in dry pyridine (65 ml) wasstirred at 100° C. for 1 hour and 30 minutes and at 120° C. foradditional 30 minutes. The reaction mixture was concentrated underreduced pressure to give an oily residue, which was dissolved in water.The resulting solution was adjusted to pH 1 with conc. hydrochloric acidto give yellow crystals, which were separated by filtration, washed withwater, and dried. The crude crystals were dissolved in a mixture ofchloroform and methanol under heating. The solution was filtered toremove insoluble materials. The solution was concentrated under reducedpressure until crystallization began and cooled. The resulting crystalswere collected by filtration and dried. There was obtained4-oxo-9-pivalamido-4H-pyrimido[1,2-C]quinazoline-3-carboxylic acid (2.9g).

mp: 252°-256° C.

IR (Nujol) νmax: 3370, 3250, 1735, 1690, 1650, 1615, 1550 cm⁻¹.

NMR δppm (DMSO-d₆): 1.30 (9H, s), 8.08 (1H, dd, J=2, 9 Hz), 8.38 (1H, d,J=2 Hz), 8.64 (1H, d, J=9 Hz), 8.86 (1H, s), 9.44 (1H, s), 9.82 (1H, s).

EXAMPLE 63

4-Oxo-10-(pivalamido)-4H-pyrimido[1,2-C]quinazoline-3-carboxylic acid(3.06 g) was suspended in N,N-dimethylformamide (60 ml). To thissuspension was added dropwise sodium hydroxide solution (sodiumhydroxide 0.36 g in water 1 ml and ethanol 7 ml) at ambient temperatureto give a clear solution. After 30 minutes, ether was added and theprecipitated crystals were collected by filtration and washed withether. The crude crystals were dissolved in water (150 ml) underheating. The solution was filtered to remove insoluble materials,diluted with acetone (800 ml), and allowed to stand at ambienttemperature. The crystals were filtered, washed with acetone, and driedto give sodium4-oxo-10-(pivalamido)-4H-pyrimido[1,2-C]quinazoline-3-carboxylate (1.73g).

mp: 318° C. (decomp).

NMR δ(D₂ O): 1.3 (9H, s), 7.4 (1H, d, J=9 Hz), 7.65 (1H, dd, J=2,9 Hz),8.15 (1H, d, J=2 Hz), 8.43 (1H, s), 9.1 (1H, s).

Anal, Cald for C₁₇ H₁₅ N₄ O₄ Na.1/3H₂ O: C, 55.44; H, 4.29; N, 15.21.Found: C, 55.55; H, 4.29; N, 15.21.

EXAMPLE 64

4-Oxo-10-(pivalamido)-4H-pyrimido[1,2-C]quinazoline-3-carboxylic acid(1.31 g) was suspended in N,N-dimethylformamide (13 ml). To thissuspension was added tris (hydroxymethyl)aminomethane (0.466 g) atambient temperature. After one hour, the starting material was dissolvedcompletely. To this solution ether was added and the precipitatedcrystals were collected by filtration and washed with ether to givetris-(hydroxymethyl)methyl-ammonium4-oxo-10-(pivalamido)-4H-pyrimido[1,2-C]quinazoline-3-carboxylate (1.63g).

mp: 180° C. (decomp).

IR (Nujol): 3150, 1725, 1665, 1610, 1570, 1530 cm⁻¹.

NMR δ(DMSO-d₆): 1.29 (9H, s), 3.5 (6H, s), 5.2 (5H, s), 7.8 (1H, d, J=9Hz), 8.25 (1H, dd, J=9, 2 Hz), 8.6 (1H, s), 9.0(1H, d, J=2 Hz), 9.26(1H, s), 9.7 (1H, s).

Anal, Cald. for C₁₇ H₁₀ N₄ O₄.C₄ H₁₁ NO₃.2H₂ O: C, 50.70; H, 6.28, N,14.09. Found: C, 51.28; H, 6.30; N, 14.49.

EXAMPLE 65

To a suspension of4-oxo-10-(2,3-dimethylpentanamido)-4H-pyrimido[1,2-C]quinazoline-3-carboxylicacid (7.3 g) in N,N-dimethylformamide (120 ml) was added methanol (140ml) under stirring at 50° C. To this solution was added dropwise sodiumhydroxide solution (sodium hydroxide 0.79 g in water 2.37 ml and ethanol15.8 ml) under stirring for 15 minutes at ambient temperature, and wasstirred for 30 minutes at ambient temperature. To this solution ether(250 ml) was added and stirred. The precipitated crystals were collectedby filtration and washed two times with water and ether, and dried underreduced pressure to give sodium4-oxo-10-(2,3-dimethylpentanamido)-4H-pyrimido[1,2-C]-quinazoline-3-carboxylate(1 hydrate) (4.4 g).

mp: 292°-296° C.

IR (Nujol) νmax: 3500, 1712, 1652, 1612, 1500 cm⁻¹.

NMR δ(CF₃ COOH): 0.8-2.2 (12H, m), 2.64 (1H, m), 8.43 (2H, m), 9.40 (3H,m).

Anal. Cald. for C₁₉ H₁₉ N₄ NaO₄.1H₂ O: C, 55.88; H, 5.18; N, 13.72.Found: C, 55.47; H, 5.06; N, 13.65.

EXAMPLE 66

To a suspension of4-oxo-10-(2,3-dimethylpentanamido)-4H-pyrimido[1,2-C]quinazoline-3-carboxylicacid (7.0 g) in N,N-dimethylformamide (93 ml) was addedtris(hydroxymethyl)aminomethane (2.3 g) and methanol (47 ml) understirring and stirred for 2 hours at ambient temperature. The insolublematerials was removed by filtration, and to the filtrate was added ether(60 ml) with stirring. The resultant precipitate was collected byfiltration and washed with ether, and dried under reduced pressure togive tris(hydroxymethyl)methylammonium4-oxo-10-(2,3-dimethylpentanamido)-4H-pyrimido[1,2-C]quinazoline-3-carboxylate(3.15 g).

mp: 172°-175° C.

IR (Nujol) νmax: 3570, 1690, 1652, 1610, 1498 cm⁻¹.

NMR δ(DMSO-d₆): 0.7-2.0 (12H, m), 2.60 (1H, m), 3.57 (6H, s), 4.5-5.7(6H, brs), 7.90 (1H, d, J=9 Hz), 8.20 (1H, dd, J=9,2 Hz), 8.70 (1H, s),9.13 (1H, d, J=2 Hz), 9.37 (1H, s), 10.43 (1H,s).

Anal. Cald. for C₂₃ H₃₁ N₅ O₇.0.5H₂ O: C, 55.41; H, 6.47; N, 14.04.Found: C, 55.49; H, 6.17; N, 13.99.

We claim:
 1. Sodium4-oxo-10-(2,3-dimethylpentanamido)-4H-pyrimido[1,2-C]quinazoline-3-carboxylate.